Endothelin antagonists

ABSTRACT

A compound of formula (I), in which: R 1  is lower alkyl, cyclo(lower)alkyl, optionally substituted aryl, optionally substituted heterocyclic group, cyclo(lower)alkyl(lower)alkyl, or ar(lower)alkyl; R 2  is hydrogen, hydroxy or protected hydroxy; R 3  is lower alkyl, aryl, ar(lower)alkyl or optionally substituted heterocyclic(lower)alkyl; R 4  is carboxy, protected carboxy or lower alkylsufonylcarbamoyl; R 5  is hydrogen or lower alkyl; R 6  is hydrogen or heterocyclic group; A is a single bond or lower alkylene, and Ar is optionally substituted aryl, or pharmaceutically acceptable salts thereof, having endothelin antagonistic activity.

TECHNICAL FIELD

The present invention relates to novel compound and a pharmaceuticallyacceptable salt thereof.

More particularly, it relates to novel compound and a pharmaceuticallyacceptable salt thereof which have pharmacological activities such asendothelin (ET) antagonistic activity and the like, to processes for itspreparation, to a pharmaceutical composition comprising the same, and toa method of using the same therapeutically in the treatment and theprevention of endothelin mediated diseases such as hypertension, and thelike.

Pharmacological and structural evidence supports the existence of atleast two endothelin receptor subtypes, i.e., ET_(A) and ET_(B). ET_(A)receptors are distributed predominantly in vascular smooth muscle, heartand intestine, whereas ET_(B) receptors are found in cerebral cortex,lung and kidney. Recently, it is found that in addition to ET_(A)receptors, vasoconstrictor ET_(B) receptors are also present on vascularsmooth muscle. ET_(A) receptors have a higher affinity to ET-1 than ET-3and sarafotoxin S6c, while ET_(B) receptors show nearly the sameaffinity to all isoforms of ET and sarafotoxin peptides.

The compounds of this invention may have ET_(A) and/or ET_(B)antagonistic activity.

One object of the present invention is to provide new and usefulcompound and a pharmaceutically acceptable salt thereof which havepharmacological activities such as endothelin, particularly ET_(A) andET_(B) dual antagonistic activity, and the like.

Another object of the present invention is to provide processes for thepreparation of said compound and a salt thereof.

A further object of the present invention is to provide a pharmaceuticalcomposition comprising, as an active ingredient, said compound or apharmaceutically acceptable salt thereof.

Still further object of the present invention is to provide a method ofusing the same for the treatment and the prevention of endothelinmediated diseases such as hypertension, and the like.

DISCLOSURE OF INVENTION

The object compound of the present invention can be represented by thefollowing general formula (I).

in which R¹ is lower alkyl, cyclo(lower)alkyl, optionally substitutedaryl, optionally substituted heterocyclic group,cyclo(lower)alkyl(lower)alkyl, or ar(lower)alkyl,

R² is hydrogen, hydroxy or protected hydroxy,

R³ is lower alkyl, aryl, ar(lower)alkyl or optionally substitutedheterocyclic(lower)alkyl,

R⁴ is carboxy, protected carboxy or lower alkylsulfonylcarbamoyl,

R⁵ is hydrogen or lower alkyl,

R⁶ is hydrogen or heterocyclic group,

A is a single bond or lower alkylene, and

Ar is optionally substituted aryl,

or pharmaceutically acceptable salts thereof.

The compound having the following formula (IA) is preferable.

Further, the compound having the relative configuration of the followingformula (IB) is more preferable.

in which R¹, R², R³, R⁴, R⁵, A and Ar are each as defined above.

According to the present invention, the novel compound (I) and a saltthereof can be prepared by the processes as shown in the followingschemes.

wherein R¹, R², R³, R⁴, R⁵, R⁶, A and Ar are each as defined above,

R_(a) ¹ is aryl substituted at least by protected carboxy; orheterocyclic group containing at least a protected imino moiety andoptionally substituted by suitable substituent(s);

R_(b) ¹ is aryl substituted at least by carboxy; or heterocyclic groupcontaining at least an imino moiety and optionally substituted bysuitable substituent(s);

R_(a) ² is protected hydroxy,

R_(a) ³ is heterocyclic(lower)alkyl substituted at least by protectedcarboxy(lower)alkyl; or heterocyclic(lower)alkyl containing at least aprotected imino moiety and optionally substituted by suitablesubstituent(s);

R_(b) ³ is heterocyclic(lower)alkyl substituted at least bycarboxy(lower)alkyl; or heterocyclic(lower)alkyl containing at least animino moiety and optionally substituted by suitable substituent(s);

R_(c) ³ is heterocyclic(lower)alkyl substituted at least bycarboxy(lower)alkyl,

R_(d) ³ is heterocyclic(lower)alkyl substituted at least by protectedcarboxy(lower)alkyl,

R_(e) ³ is heterocyclic(lower)alkyl containing at least a thia moietyand optionally substituted by suitable substituent(s),

R_(f) ³ is heterocyclic(lower)alkyl containing at least thia moiety andits dioxide, and optionally substituted by suitable substituent(s),

R_(a) ⁴ is protected carboxy,

Ar¹ is aryl substituted by the group consisting of protected hydroxy andprotected carboxy, and optionally by suitable substituent(s), and

Ar² is aryl substituted by the group consisting of hydroxy and carboxy,and optionally by suitable substituent(s).

Some of the starting compounds used in the above Processes are novel andcan be prepared according to the procedures described in the followingPreparations and/or by a conventional manner.

Suitable pharmaceutically acceptable salts of the object compound (I)may be a conventional non-toxic salt and include an acid addition saltsuch as an organic acid salt (e.g. acetate, trifluoroacetate, maleate,tartrate fumarate, methanesulfonate, benzenesulfonate, formate,toluenesulfonate, etc.), an inorganic acid salt (e.g. hydrochloride,hydrobromide, hydriodide, sulfate, nitrate, phosphate, etc.), or a saltwith a base such as an amino acid (e.g. arginine, aspartic acid,glutamic acid, etc.), an alkali metal salt (e.g. sodium salt, potassiumsalt, etc.), an alkaline earth metal salt (e.g. calcium salt, magnesiumsalt, etc.), an ammonium salt, an organic base salt (e.g. trimethylaminesalt, triethylamine salt, pyridine salt, picoline salt,dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt, etc.), or thelike.

In the above and subsequent descriptions of the present specification,suitable examples and illustrations of the various definitions which thepresent invention includes within the scope thereof are explained indetail as follows.

The term “lower” is intended to mean 1 to 6, preferably 1 to 4 carbonatoms, unless otherwise indicated.

Suitable “cyclo(lower)alkyl” may include cyclo-(C₃-C₇)alkyl such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, in whichthe most preferred example may be cyclopropyl and cyclohexyl.

Suitable “lower alkyl” may include a straight or branched one such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,1-ethylpropyl, pentyl, neopentyl, hexyl, and the like, in which the mostpreferable one may be ethyl, propyl, isopropyl, butyl, pentyl,1-ethylpropyl, isobutyl and neopentyl as R¹, and isobutyl as R³.

Suitable “protected carboxy” may include esterified carboxy wherein“esterified carboxy” can be referred to the ones as mentioned below.

Suitable examples of the ester moiety of an esterified carboxy may bethe ones such as lower alkyl ester (e.g. methyl ester, ethyl ester,propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butylester, pentyl ester, hexyl ester, etc.) which may have at least onesuitable substituent(s), for example, lower alkanoyloxy(lower)alkylester [e.g. acetoxymethyl ester, propionyloxymethyl ester,butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester,hexanoyloxymethyl ester, 1-(or 2-)acetoxyethyl ester, 1-(or 2- or3-)acetoxypropyl ester, 1-(or 2- or 3- or 4-)-acetoxybutyl ester, 1-(or2-)propionyloxyethyl ester, 1-(or 2- or 3-)propionyloxypropyl ester,1-(or 2-)-butyryloxyethyl ester, 1-(or 2-)isobutyryloxyethyl ester,1-(or 2-)pyvaloyloxyethyl ester, 1-(or 2-)hexanoyloxyethyl esterisobutyryloxymethyl ester, 2-ethylbutyryloxymethyl ester,3,3-dimethylbutyryloxymethyl ester, 1-(or 2-)-pentanoyloxyethyl ester,etc.], lower alkanesulfonyl(lower)alkyl ester (e.g. 2-mesylethyl ester,etc.), mono(or di or tri)halo(lower)alkyl ester (e.g. 2-iodoethyl ester,2,2,2-trichloroethyl ester, etc.); lower alkoxycarbonyloxy(lower)alkylester [e.g. methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethylester, propoxycarbonyloxymethyl ester, t-butoxycarbonyloxymethyl ester,1-(or 2-)-methoxycarbonyloxyethyl ester, 1-(or2-)-ethoxycarbonyloxyethyl ester, 1-(or 2-)-isopropoxycarbonyloxyethylester, etc.], phthalidylidene(lower)alkyl ester, or (5-loweralkyl-2-oxo-1,3-dioxol-4-yl)(lower)alkyl ester [e.g.(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester,(5-ethyl-2-oxo-1,3-dioxol-4-yl)methyl ester,(5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, etc.]; lower alkenyl ester(e.g. vinyl ester, allyl ester, etc.); lower alkynyl ester (e.g. ethynylester, propynyl ester, etc.); ar(lower)alkyl ester which may have atleast one suitable substituent(s) (e.g. benzyl ester, 4-methoxybenzylester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydrylester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester,4-hydroxy-3,5-di-t-butylbenzyl ester, etc.); aryl ester which may haveat least one suitable substituent(s) (e.g. phenyl ester, 4-chlorophenylester, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester,cumenyl ester, etc.); phthalidyl ester; and the like.

More preferable example of the protected carboxy thus defined may belower alkoxycarbonyl and phenyl(or nitrophenyl)(C₁-C₄)alkoxycarbonyl,and the most preferable one may be methoxycarbonyl, ethoxycarbonyl andbenzyloxycarbonyl.

Suitable heterocyclic group moiety of “optionally substitutedheterocyclic group” or “optionally substituted heterocyclic(lower)alkyl”means saturated or unsaturated, monocyclic or polycyclic heterocyclicgroup containing at least one hetero-atom such as an oxygen, sulfur,nitrogen atom and the like.

More preferable heterocyclic group may be:

unsaturated condensed (preferably bicyclic) 7- to 12-membered,preferably 9- or 10-membered, heterocyclic group containing 1 to 5nitrogen atom(s), for example, indolyl, isoindolyl, indolizinyl,benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl,tetrazolopyridyl, tetrazolopyridazinyl (e.g.,tetrazolo[1,5-b]pyridazinyl, etc.), dihydrotriazolopyridazinyl, etc.;

unsaturated condensed (preferably bicyclic) 7- to 12-membered,preferably 9- or 10-membered heterocyclic group containing 1 to 3 sulfuratoms or its S,S-dioxide, for example, dithianaphthalenyl (e.g.4H-1,3-dithianaphthalenyl, 1,4-dithianaphthalenyl, etc.),benzothiophenyl or its S,S-dioxide (e.g. benzo[a]thiophenyl or itsS,S-dioxide, benzo[b]thiophenyl or its S,S-dioxide, etc.), etc.,

unsaturated 3- to 8-membered, preferably 5- or 6-memberedheteromonocyclic group containing 1 to 4 nitrogen atom(s), for example,pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, and its N-oxide,pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl,1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g.,1H-tetrazolyl, 2H-tetrazolyl, etc.), dihydrotriazinyl (e.g.,4,5-dihydro-1,2,4-triazinyl, 2,5-dihydro-1,2,4-triazinyl, etc.), etc.;

saturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclicgroup containing 1 to 4 nitrogen atom(s), for example, azetidinyl,pyrrolidinyl, imidazolidinyl, piperidinyl, pyrazolidinyl, piperazinyl,etc.;

unsaturated condensed (preferably bicyclic) 7- to 12-membered,preferably 9- or 10-membered, heterocyclic group containing 1 to 2oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl,benzoxadiazolyl, etc.;

unsaturated 3- to 8-membered, preferably 5- or 6-memberedheteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl, (e.g.,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.;

saturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclicgroup containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), forexample, morpholinyl, etc.;

unsaturated condensed (preferably bicyclic) 7- to 12-membered,preferably 9- or 10-membered heterocyclic group containing 1 to 2 sulfuratom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl,benzothiadiazolyl, etc.

unsaturated 3- to 8-membered, preferably 5- or 6-memberedheteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3nitrogen atom(s), for example, thiazolyl, 1,2-thiazolyl, thiazolyl,thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl), etc.;

saturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclicgroup containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), forexample, thiazolidinyl, etc.;

unsaturated 3- to 8-membered, preferably 5- or 6-memberedheteromonocyclic group containing a sulfur atom, for example, thienyl,etc.; and the like;

wherein said heterocyclic group may be substituted by one or more,preferably one or two suitable substituent(s) such as

hydroxy;

protected hydroxy, in which the hydroxy group is protected by aconventional hydroxy-protective group such as acyl, ar(lower)alkyl asmentioned below (e.g. benzyl, etc.), tri(lower)alkylsilyl, etc.;

halogen such as chlorine, bromine, iodine, fluorine, etc.;

lower alkoxy, which may be straight or branched one such as methoxy,ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, etc., morepreferably C₁-C₄ alkoxy (e.g. methoxy, etc.);

carboxy;

protected carboxy such as lower alkoxycarbonyl (e.g. methoxycarbonyl,t-butoxycarbonyl, etc.), phenyl (or nitrophenyl)(lower)alkoxycarbonyl(e.g. benzyloxycarbonyl, etc.), etc.;

lower alkylenedioxy, more preferably C₁-C₄ alkylenedioxy (e.g.methylenedioxy, ethylenedioxy, etc.);

carbamoyl(lower)alkyl (e.g. carbamoylmethyl, etc.);

N- or N,N-di(lower)alkylcarbamoyl(lower)alkyl, preferablyN,N-di(C₁-C₄)alkylcarbamoyl(C₁-C₄)alkyl (e.g.N,N-dimethylcarbamoylmethyl, etc.);

carboxy(lower)alkyl, preferably carboxy(C₁-C₄)alkyl (e.g. carboxymethyl,2-carboxyethyl, etc.);

protected carboxy(lower)alkyl such as lower alkoxycarbonyl(lower)alkyl(e.g. methoxycarbonylmethyl, 2-ethoxycarbonylethyl,t-butoxycarbonylmethyl, 2-ethoxycarbonylethyl, etc.),ar(lower)alkoxycarbonyl(lower)alkyl (e.g. benzyloxycarbonylmethyl,etc.), etc.;

C₆-C₁₀ ar(lower)alkyl such as mono- or di- or triphenyl(lower)alkyl(e.g. triphenylmethyl, etc.);

halo(lower)alkyl, which is aforementioned lower alkyl group substitutedby one or more, preferably one to three halogen as mentioned above;

halo(lower)alkoxy, which is hydroxy group substituted by aforementionedhalo(lower)alkyl;

lower alkanoyl as mentioned below (e.g. formyl, etc.);

lower alkyl as mentioned above, more preferably C₁-C₄ alkyl (e.g.methyl, ethyl, isopropyl,, etc.); -amino; -nitro; -cyano; and the like.

And further when said heterocyclic group has imino-moiety(ies) in itsring, the imino-moiety(ies) may be substituted by suitablesubstituent(s) such as;

-imino-protective group such as acyl, more preferably lower alkanoyl(e.g. formyl, acetyl, etc.) lower alkoxycarbonyl (e.g. t-butoxycarbonyl,etc.), nitroar(lower)alkoxycarbonyl; and the like.

Preferable examples of optionally substituted heterocyclic(lower)alkylthus defined may be lower alkyl substituted by unsaturated 9- or10-membered bicyclic heterocyclic group containing 1 to 5 nitrogenatom(s) (e.g. indolyl, etc.) optionally substituted by lower alkanoyl,carbamoyl(lower)alkyl, N- or N,N-di(lower)alkylcarbamoyl(lower)alkyl,hydroxy, C₆-C₁₀ ar(lower)alkoxy, lower alkoxy, carboxy, loweralkoxycarbonyl(lower)alkyl, carboxy(lower)alkyl,ar(lower)alkoxycarbonyl(lower)alkyl, lower alkoxycarbonyl,phenyl(lower)alkoxycarbonyl, lower alkylenedioxy or lower alkyl; loweralkyl substituted by unsaturated 9- or 10-membered bicyclic heterocyclicgroup containing 1 to 3 sulfur atoms or its S,S-dioxide (e.g.benzothiophenyl, benzothiophenyl S,S-dioxide, etc.) optionallysubstituted by lower alkanoyl, carbamoyl(lower)alkanoyl, N- orN,N-di(lower)alkylcarbamoyl(lower)alkyl, hydroxy, C₆-C₁₀ar(lower)alkoxy, lower alkoxy, carboxy, loweralkoxycarbonyl(lower)alkyl, carboxy(lower)alkyl,ar(lower)alkoxycarbonyl(lower)alkyl, lower alkoxycarbonyl,phenyl(lower)alkoxycarbonyl, lower alkylenedioxy or lower alkyl; inwhich the most preferable one may be indol-3-ylmethyl optionally 4-, 5-,6-, or 7-substituted by methyl or optionally N-substituted by the groupconsisting of methyl, ethyl, isopropyl, formyl, carbamoylmethyl,N,N-dimethylcarbamoylmethyl, methoxycarbonyl, methoxycarbonylmethyl,ethoxycarbonylmethyl, t-butoxycarbonylmethyl, 2-ethoxycarbonylethyl,benzyloxycarbonylmethyl, carboxymethyl and 2-carboxyethyl, andbenzo[b]thiophen-3-ylmethyl or its S,S-dioxide as R³.

Preferable examples of “heterocyclic group” or “optionally substitutedheterocyclic group” thus defined may be unsaturated 5- or 6- memberedheteromonocyclic group containing 1 to 4 nitrogen atom(s) (e.g. pyridyl,imidazolyl, etc.), optionally substituted by hydroxy, C₆-C₁₀ar(lower)alkoxy, lower alkoxy, carboxy, lower alkoxycarbonyl,phenyl(lower)alkoxycarbonyl, triphenyl(lower)alkyl, lower alkylenedioxyor lower alkyl, in which the most preferable one may be pyridin-2-yl,and imidazol-4(or 5)-yl optionally substituted by the group consistingof methyl, ethyl, propyl, butyl, pentyl, triphenylmethyl andt-butoxycarbonyl as R¹ and pyridin-2-yl as R⁶.

Suitable “lower alkylene” means straight or branched one such asmethylene, ethylene, trimethylene, methylethylene, and the like, inwhich more preferable example may be C₁-C₄ alkylene, and the mostpreferable one may be methylene and ethylene.

Suitable aryl moiety of “aryl” or “optionally substituted aryl” mayinclude C₆-C₁₀ aryl such as phenyl, tolyl, xylyl, cumenyl, naphthyl, andthe like, wherein said aryl may be substituted by suitablesubstituent(s) such as those mentioned in the explanation of “optionallysubstituted heterocyclic group” as mentioned above, and aryl asmentioned above, and the like.

Preferable examples of aryl or optionally substituted aryl thus definedmay be phenyl and naphthyl, each of which being optionally substitutedby hydroxy, protected hydroxy as mentioned below (e.g. C₆-C₁₀ar(lower)alkoxy, etc.), lower alkylenedioxy, carboxy, protected carboxy(e.g. lower alkoxycarbonyl, C₆-C₁₀ ar(lower)alkoxycarbonyl, etc.), loweralkoxy, aryl, and the like, in which the most preferable one may bephenyl, 3,4-methylenedioxyphenyl, 4-carboxyphenyl,4-methoxycarbonylphenyl, 3,4,5-trimethoxyphenyl and 4-(or 2-)biphenylylas R¹, phenyl as R³, and 2-hydroxyphenyl, 2-benzyloxyphenyl,2-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4-methylenedioxyphenyl,3,4-ethylenedioxyphenyl, 2-(or 4-)carboxyphenyl,4-methoxycarbonylphenyl, 2-benzyloxycarbonylphenyl and 2-naphthyl as Ar.

Preferable “protected hydroxy” means hydroxy group protected by aconventional hydroxy-protective group such as acyl as mentioned below;(C₆-C₁₀)ar(lower)alkyl such as mono- or di- or triphenyl(lower)alkyl(e.g. benzyl, benzhydryl, trityl, etc.), etc.; trisubstituted silyl suchas tri(lower)alkylsilyl (e.g. trimethylsilyl, triethylsilyl,isopropyldimethylsilyl, t-butyldimethylsilyl, diisopropylmethylsilyl,etc.), tri(C₆-C₁₀)arylsilyl (e.g. triphenylsilyl, etc.),tris[(C₆-C₁₀)ar(lower)alkyl]silyl, for example,tris[phenyl(lower)alkyl]silyl (e.g. tribenzylsilyl, etc.), etc.; and thelike, in which more preferable example may be lower alkanoyloxy andC₆-C₁₀ ar(lower)alkoxy, and the most preferable one may be acetoxy as R²and benzyloxy in Ar.

Preferable acyl may include aliphatic acyl, aromatic acyl, heterocyclicacyl and aliphatic acyl substituted with aromatic or heterocyclicgroup(s) derived from carboxylic, carbonic, sulfonic and carbamic acids.

The aliphatic acyl may include saturated or unsaturated, acyclic orcyclic ones, for example, alkanoyl such as lower alkanoyl (e.g. formyl,acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl,hexanoyl, etc.), alkylsulfonyl such as lower alkylsulfonyl (e.g. mesyl,ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl,isobutylsulfonyl, pentylsulfonyl, hexylsulfonyl, etc.), carbamoyl,N-alkylcarbamoyl (e.g. methylcarbamoyl, ethylcarbamoyl, etc.),alkoxycarbonyl such as lower alkoxycarbonyl (e.g. methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl,etc.), alkenyloxycarbonyl such as lower alkenyloxycarbonyl (e.g.vinyloxycarbonyl, allyloxycarbonyl, etc.), alkenoyl such as loweralkenoyl (e.g. acryloyl, methacryloyl, crotonoyl, etc.),cycloalkanecarbonyl such as cyclo(lower)alkanecarbonyl (e.g.cyclopropanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, etc.),and the like.

The aromatic acyl may include C₆-C₁₀ aroyl (e.g. benzoyl, toluoyl,xyloyl, etc.), N-(C₆-C₁₀)arylcarbamoyl (e.g. N-phenylcarbamoyl,N-tolylcarbamoyl, N-naphthylcarbamoyl, etc.), C₆-C₁₀ arenesulfonyl (e.g.benzenesulfonyl, tosyl, etc.), and the like.

The aliphatic acyl substituted with aromatic group(s) may includearalkoxycarbonyl such as phenyl(lower)alkoxycarbonyl (e.g.benzyloxycarbonyl, phenethyloxycarbonyl, etc.), and the like.

These acyl groups may be further substituted with one or more suitablesubstituent(s) such as nitro, and the like, and preferable acyl havingsuch substituent(s) may be nitroaralkoxycarbonyl (e.g.nitrobenzyloxycarbonyl, etc.), and the like.

Suitable “cyclo(lower)alkyl(lower)alkyl” means aforementioned loweralkyl which is substituted by C₃-C₇ cyclo(lower)alkyl such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and thelike, wherein more preferable example may be C₄-C₆cyclo(lower)alkyl(lower)alkyl and the most preferable one may becyclohexylmethyl.

Suitable “ar(lower)alkyl” may include C₆-C₁₀ ar(lower)alkyl such asphenyl(lower)alkyl (e.g. benzyl, phenethyl, etc.), tolyl(lower)alkyl,xylyl(lower)alkyl, cumenyl(lower)alkyl, naphthyl(lower)alkyl, and thelike, in which more preferable example may be phenyl(C₁-C₄)alkyl, andthe most preferable one may be benzyl as R¹ or R³, 1-(or2-)-naphthylmethyl as R³.

Suitable “lower alkoxy” means conventional straight or branched one suchas methoxy, ethoxy, propoxy, butoxy, t-butoxy, pentyloxy, hexyloxy, andthe like, in which the most preferable example may be methoxy.

Suitable “lower alkylsulfonylcarbamoyl” may include carbamoylsubstituted by lower alkylsulfonyl such as methyl sulfonyl, etc., inwhich more preferable example may be C₁-C₄ alkylsulfonylcarbamoyl, andthe most preferable one may be methylsulfonylcarbamoyl.

Preferred embodiment of R¹, R², R³, R⁴, R⁵, R⁶, A and Ar may be:

R¹ is cyclo(C₃-C₇)alkyl,

R² is hydroxy,

R³ is lower alkyl substituted by unsaturated bicyclic 7- to 12-memberedheterocyclic group containing 1 to 5 nitrogen atom(s), optionallyN-substituted by lower alkyl (e.g. indol-3-ylmethyl optionallyN-substituted by methyl, etc.),

R⁴ is carboxy or C₆-C₁₀ ar(lower)alkoxycarbonyl,

R⁵ is hydrogen,

R⁶ is hydrogen,

A is a single bond or lower alkylene, and

Ar is phenyl, hydroxyphenyl, C₆-C₁₀ ar(lower)alkoxyphenyl, loweralkoxyphenyl, carboxyphenyl or C₆-C₁₀ ar(lower)alkoxycarbonylphenyl.

Another preferred embodiment of R¹, R², R³, R⁴, R⁵, R⁶, A and Ar may be:

R¹ is lower alkyl, cyclo(lower)alkyl, aryl optionally substituted by thegroup consisting of lower alkylenedioxy, carboxy, lower alkoxycarbonyl,lower alkoxy and aryl, unsaturated 5- or 6-membered heteromonocyclicgroup containing 1 to 4 nitrogen atom(s) optionally substituted by thegroup consisting of lower alkyl and lower alkoxycarbonyl,cyclo(lower)alkyl(lower)alkyl, or ar(lower)alkyl,

R² is hydrogen or hydroxy,

R³ is lower alkyl, aryl, ar(lower)alkyl, lower alkyl substituted byunsaturated 9- or 10-membered bicyclic heterocyclic group containing 1to 5 nitrogen atom(s), said heterocyclic group being optionallysubstituted by lower alkyl,

R⁴ is carboxy, lower alkoxycarbonyl or C₆-C₁₀ ar(lower)-alkoxycarbonyl,

R⁵ is hydrogen,

R⁶ is hydrogen,

A is single bond or lower alkylene, and

Ar is aryl optionally substituted by the group consisting of hydroxy,C₆-C₁₀ ar(lower)alkoxy, lower alkylenedioxy, carboxy, C₆-C₁₀ar(lower)alkoxycarbonyl and lower alkoxy.

A further preferred embodiment of R¹, R², R³, R⁴, R⁵, R⁶, A and Ar maybe:

R¹ is lower alkyl, cyclo(lower)alkyl, aryl optionally substituted by thegroup consisting of lower alkylenedioxy, carboxy, lower alkoxycarbonyl,lower alkoxy and aryl, unsaturated 5- or 6-membered heteromonocyclicgroup containing 1 to 4 nitrogen atom(s) optionally substituted by thegroup consisting of lower alkyl, lower alkoxycarbonyl andtriphenyl(lower)alkyl, cyclo(lower)alkyl(lower)alkyl, or ar (lower)alkyl,

R² is hydrogen, hydroxy or protected hydroxy,

R³ is lower alkyl, C₆-C₁₀ aryl, C₆-C₁₀ ar(lower)alkyl, lower alkylsubstituted by the group consisting of unsaturated 9- or 10 memberedbicyclic heterocyclic group containing 1 to 5 nitrogen atom(s), saidheterocyclic group being optionally 4-, 5-, 6- or 7-substituted by loweralkyl or optionally N-substituted by the group consisting of loweralkyl, carbamoyl(lower)alkyl, N,N-di(lower)alkylcarbamoyl, loweralkoxycarbonyl, carboxy(lower)alkyl, lower alkoxycarbonyl(lower)alkyland C₆-C₁₀ ar(lower)alkoxycarbonyl(lower)alkyl, lower alkyl substitutedby unsaturated 9- or 10-membered bicyclic heterocyclic group containing1 to 3 sulfur atom(s) or its S,S-dioxide,

R⁴ is carboxy, lower alkoxycarbonyl, C₆-C₁₀ ar(lower)alkoxycarbonyl orlower alkylsulfonylcarbamoyl,

R⁵ is hydrogen,

R⁶ is hydrogen or unsaturated 5- or 6-membered hetero-monocyclic groupcontaining 1 to 4 nitrogen atom(s),

A is a single bond or lower alkylene, and

Ar is C₆-C₁₀ aryl optionally substituted by the group consisting ofhydroxy, C₆-C₁₀ ar(lower)alkoxy, lower alkylenedioxy, carboxy, C₆-C₁₀ar(lower)alkoxycarbonyl and lower alkoxy.

The processes for preparing the object compound (I) are explained indetail in the following.

Process 1

The object compound (I) or a salt thereof can be prepared by reactingthe compound (II) or its reactive derivative at the carboxy group, or asalt thereof with the compound (III) or its reactive derivative at theamino group, or a salt thereof.

Suitable reactive derivative at the amino group of the compound (III)may include Schiff's base type imino or its tautomeric enamine typeisomer formed by the reaction of the compound (III) with a carbonylcompound such as aldehyde, ketone or the like; a silyl derivative formedby the reaction of the compound (III) with a silyl compound such asbis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide,bis(trimethylsilyl)urea or the like; a derivative formed by reaction ofthe compound (III) with phosphorus trichloride or phosgene, and thelike.

Suitable salts of the compound (III) and its reactive derivative can bereferred to the acid addition salts as exemplified for the compound (I).

Suitable reactive derivative at the carboxy group of the compound (II)may include an acid halide, an acid anhydride, an activated amide, anactivated ester, and the like. Suitable examples of the reactivederivatives may be an acid chloride; an acid azide; a mixed acidanhydride with acid such as substituted phosphoric acid [e.g.dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid,dibenzylphosphoric acid, halogenated phosphoric acid, etc.],dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuricacid, sulfonic acid [e.g. methanesulfonic acid, etc.], aliphaticcarboxylic acid [e.g. acetic acid, propionic acid, butyric acid,isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid,2-ethylbutyric acid, trichloroacetic acid, etc.] or aromatic carboxylicacid [e.g. benzoic acid, etc.]; a symmetrical acid anhydride; anactivated amide with imidazole, 4-substituted imidazole,dimethylpyrazole, triazole or tetrazole; or an activated ester [e.g.cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl

ester, vinyl ester, propargyl ester, p-nitrophenyl ester,2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester,mesylphenyl ester, phenylazophenyl ester, phenyl thioester,p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester,pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester,etc.], or an ester with a N-hydroxy compound [e.g.N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone,N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole,etc.], and the like.

These reactive derivatives can optionally be selected from themaccording to the kind of the compound (II) to be used.

Suitable salts of the compound (II) and its reactive derivative may be abase salt such as an alkali metal salt [e.g. sodium salt, potassiumsalt, etc.], an alkaline earth metal salt [e.g. calcium salt, magnesiumsalt, etc.], an ammonium salt, an organic base salt [e.g. trimethylaminesalt, triethylamine salt, pyridine salt, picoline salt,dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt, etc.] or thelike.

The reaction is usually carried out in a conventional solvent such aswater, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane,acetonitrile, chloroform, methylene chloride, ethylene chloride,tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or anyother organic solvent which does not adversely influence the reaction.These conventional solvent may also be used in a mixture with water.

In this reaction, when the compound (II) is used in a free acid form orits salt form, the reaction is preferably carried out in the presence ofa conventional condensing agent such as N,N′-dicyclohexylcarbodiimide;N-cyclohexyl-N′-morpholinoethylcarbodiimide;N-cyclohexyl-N′-(4-diethylaminocyclohexyl)carboxiimide;N,N′-diethylcarbodiimide, N,N′-diisopropylcarbodiimide;N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide;N,N′-carbonylbis(2-methylimidazole);pentamethyleneketene-N-cyclohexylimine;diphenylketene-N-cyclohexylimine; ethoxyacetylene;1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate;isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride);phosphorus trichloride; diphenyl phosphorylazide; thionyl chloride;oxalyl chloride; lower alkyl haloformate [e.g. ethyl chloroformate,isopropyl chloroformate, etc.]; triphenylphosphine;2-ethyl-7-hydroxybenzisoxazolium salt;2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt;N-hydroxybenzotriazole;1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; so-calledVilsmeier reagent prepared by the reaction of N,N-dimethylformamide withthionyl chloride, phosgene, trichloromethyl chloroformate, phosphorusoxychloride, etc.; or the like.

The reaction may also be carried out in the presence of an inorganic ororganic base such as an alkali metal bicarbonate, tri(lower)alkylamine,pyridine, N-(lower)alkylmorpholine (e.g. N-methylmorpholine, etc.),N,N-di(lower)alkylbenzylamine, or the like.

The reaction temperature is not critical, and the reaction is usuallycarried out under cooling to warming.

Process 2

The object compound (I-b) or a salt thereof can be prepared bysubjecting the compound (I-a) or a salt thereof to a removal reaction ofthe hydroxy- or carboxy-protective group in Ar¹.

Suitable salts of the compounds (I-a) and (I-b) can be referred to theones as exemplified for the compound (I).

This reaction is carried out in accordance with a conventional methodsuch as hydrolysis, reduction, or the like.

This hydrolysis is preferably carried out in the presence of a base oran acid.

Suitable base may include an inorganic base and an organic base such asan alkali metal [e.g. sodium, potassium, etc.], an alkaline earth metal[e.g. magnesium, calcium, etc.], the hydroxide or carbonate orbicarbonate thereof, hydrazine, trialkylamine [e.g. trimethylamine,triethylamine, etc.], picoline, 1,5-diazabicyclo[4.3.0]non-5-ene,1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, orthe like.

Suitable acid may include an organic acid [e.g. formic acid, aceticacid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.],an inorganic acid [e.g. hydrochloric acid, hydrobromic acid, sulfuricacid, hydrogen chloride, hydrogen bromide, hydrogen fluoride, etc.].

The reaction is usually carried out in a solvent such as water, analcohol [e.g. methanol, ethanol, etc.], methylene chloride, chloroform,carbon tetrachloride, tetrahydrofuran, N,N-dimethylformamide, a mixturethereof or any other solvent which does not adversely influence thereaction. A liquid base or acid can be also used as the solvent.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to heating.

The reduction method applicable for the removal reaction may includechemical reduction and catalytic reduction.

Suitable reducing agents to be used in chemical reduction are acombination of metal [e.g. tin, zinc, iron, etc.] or metallic compound[e.g. chromium chloride, chromium acetate, etc.] and an organic orinorganic acid [e.g. formic acid, acetic acid, propionic acid,trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid,hydrobromic acid, etc.].

Suitable catalysts to be used in catalytic reduction are conventionalones such as platinum catalysts [e.g. platinum plate, spongy platinum,platinum black, colloidal platinum, platinum oxide, platinum wire,etc.], palladium catalysts [e.g. spongy palladium, palladium black,palladium oxide, palladium on carbon, colloidal palladium, palladium onbarium sulfate, palladium on barium carbonate, etc.], nickel catalysts[e.g. reduced nickel, nickel oxide, Raney nickel, etc.], cobaltcatalysts [e.g. reduced cobalt, Raney cobalt, etc.], iron catalysts[e.g. reduced iron, Raney iron, etc.], copper catalysts [e.g. reducedcopper, Raney copper, Ullman copper, etc.] and the like.

The reduction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as water, methanol,ethanol, propanol, N,N-dimethylformamide, or a mixture thereof.Additionally, in case that the above-mentioned acid to be used inchemical reduction are in liquid, they can also be used as a solvent.Further, a suitable solvent to be used in catalytic reduction may be theabove-mentioned solvent, and other conventional solvent such as diethylether, dioxane, tetrahydrofuran, etc., or a mixture thereof.

The reaction temperature of this reduction is not critical and thereaction is usually carried out under cooling to heating.

Process 3

The object compound (I-d) or a salt thereof can be prepared bysubjecting the compound (I-c) or a salt thereof to a removal reaction ofthe carboxy-protective group(s) in R_(a) ⁴.

Suitable salts of the compounds (I-c) and (I-d) can be referred to theones as exemplified for the compound (I).

This removal reaction can be carried out by a conventional method inthis field such as hydrolysis, reduction, and the like, and the detailsof which can be referred to those of Process 2.

Process 4

The object compound (I-f) or a salt thereof can be prepared bysubjecting the compound (I-e) or a salt thereof to a removal reaction ofthe imino- and/or carboxy-protective group(s) in R_(a) ¹.

Suitable salts of the compounds (I-e) and (I-f) can be referred to theones as exemplified for the compound (I).

This removal reaction can be carried out by a conventional method inthis field such as hydrolysis, reduction, and the like, and the detailsof which can be referred to those of Process 2.

Process 5

The object compound (I-h) or a salt thereof can be prepared bysubjecting the compound (I-g) or a salt thereof to a removal reaction ofthe carboxy-protective group in R_(a) ³.

Suitable salts of the compounds (I-g) and (I-h) can be referred to theones as exemplified for the compound (I).

This removal reaction can be carried out by a conventional method inthis field such as hydrolysis, reduction, and the like, and the detailsof which can be referred to those of Process 2.

Process 6

The object compound (I-c) or a salt thereof can be prepared byintroducing a carboxy-protective group into the compound (I-d) or a saltthereof.

This reaction can be carried out by a conventional method used in thisfield which can introduce a conventional carboxy-protective group asmentioned above, such as reacting with alcohol or its reactiveequivalence (e.g. halide thereof, etc.) in the presence of a suitablebase as mentioned above, or by reacting withtri(lower)alkylsilyldiazomethane (e.g. trimethylsilyldiazomethane, etc.)in the presence of a suitable alcohol (e.g. methanol, etc.).

The reduction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as benzene, hexane,alcohol (e.g. methanol, ethanol, propanol, etc.), N,N-dimethylformamide,diethyl ether, dioxane, tetrahydrofuran, etc., or a mixture thereof.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling o heating.

Process 7

The object compound (I-j) or a salt thereof can be prepared byintroducing a carboxy-protective group into R_(c) ³ of the compound(I-i) or a salt thereof.

Suitable salts of the compounds (I-i) and (I-j) can be referred to theones as exemplified for the compound (I).

This removal reaction can be carried out in a similar manner as that ofProcess 6, therefore the details of which can be referred to those ofProcess 6.

Process 8

The compound (I-l) or a salt thereof can be prepared by introducing ahydroxy-protective group into the compound (I-k) or a salt thereof.

Suitable salts of the compounds (I-k) and (I-l) may be the same as thosefor the compound (I).

Suitable introducing agent of the hydroxy-protective group used in thisreaction may be a conventional acylating agent which is capable ofintroducing the acyl group as mentioned before such as carboxylic acid,carbonic acid, sulfonic acid and their reactive derivative, for example,an acid halide, an acid anhydride, an activated amide, an activatedester, and the like.

Preferable example of such reactive derivative may include acidchloride, acid bromide, a mixed acid anhydride with an acid such assubstituted phosphoric acid (e.g. dialkylphosphoric acid,phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid,halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfurousacid, thiosulfuric acid, sulfuric acid, alkyl carbonate (e.g. methylcarbonate, ethyl carbonate, propyl carbonate, etc.), aliphaticcarboxylic acid (e.g. pivalic acid, pentanoic acid, isopentanoic acid,2-ethylbutyric acid, trichloroacetic acid, etc.), aromatic carboxylicacid (e.g. benzoic acid, etc.), a symmetrical acid anhydride, anactivated acid amide with a heterocyclic compound containing iminofunction such as imidazole, 4-substituted imidazole, dimethylpyrazole,triazole and tetrazole, an activated ester (e.g. p-nitrophenyl ester,2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester,mesylphenyl ester, phenylazophenyl ester, phenyl thioester,p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester,pyridyl ester, piperidinyl ester, 8-quinolyl thioester, or an ester witha N-hydroxy compound such as N,N-dimethylhydroxylamine,1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide,1-hydroxybenzotriazole, 1-hydroxy-6-chlorobenzotriazole, etc.), and thelike.

This reaction can be carried out in the presence of an organic orinorganic base such as alkali metal (e.g. lithium, sodium, potassium,etc.), alkaline earth metal (e.g. calcium, etc.), alkali metal hydride(e.g. sodium hydride, etc.), alkaline earth metal hydride (e.g. calciumhydride, etc.), alkali metal hydroxide (e.g. sodium hydroxide, potassiumhydroxide, etc.), alkali metal carbonate (e.g. sodium carbonate,potassium carbonate, etc.), alkali metal bicarbonate (e.g. sodiumbicarbonate, potassium bicarbonate, etc.), alkali metal alkoxide (e.g.sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.),alkali metal alkanoic acid (e.g. sodium acetate, etc.), trialkylamine(e.g. triethylamine, etc.), pyridine compound (e.g. pyridine, lutidine,picoline, 4-dimethylaminopyridine, etc.), quinoline, and the like.

In case that the introducing agent of the hydroxy-protective group isused in a free form or its salt in this reaction, the reaction ispreferably carried out in the presence of a condensing agent such as acarbodiimide compound [e.g. N,N′-dicyclohexylcarbodiimide,N-cyclohexyl-N′-(4-diethylaminocyclohexyl)carbodiimide,N,N′-diethylcarbodiimide, N,N′-diisopropylcarbodiimide,N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide, etc.], a keteniminecompound (e.g. N,N′-carbonylbis(2-methylimidazole),pentamethyleneketene-N-cyclohexylimine,diphenylketene-N-cyclohexylimine, etc.); an olefinic or acetylenic ethercompounds (e.g. ethoxyacetylene, β-chlorovinylethyl ether), a sulfonicacid ester of N-hydroxybenzotriazole derivative [e.g.1-(4-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole, etc.], acombination of trialkylphosphite or triphenylphosphine and carbontetrachloride, disulfide or diazenedicarboxylate (e.g. diethyldiazenedicarboxylate, etc.), a phosphorus compound (e.g. ethylpolyphosphate, isopropyl polyphosphate, phosphoryl chloride, phosphorustrichloride, etc.), thionyl chloride, oxalyl chloride,N-ethylbenzisoxazolium salt, N-ethyl-5-phenylisoxazolium-3-sulfonate, areagent (referred to as so-called “Vilsmeier reagent”) formed by thereaction of an amide compound such as N,N-di(lower)alkylformamide (e.g.dimethylformamide, etc.), N-methylformamide or the like with a halogencompound such as thionyl chloride, phosphoryl chloride, phosgene or thelike.

The reaction is usually carried out in a conventional solvent which doesnot adversely influence the reaction such as water, acetone,dichloromethane, alcohol (e.g. methanol, ethanol, etc.),tetrahydrofuran, pyridine, N,N-dimethylformamide, etc., or a mixturethereof, and further in case that the hydroxy-protective groupintroducing agent is in liquid, it can also be used as a solvent.

The reaction temperature is not critical and the reaction is usuallycarried out under from cooling to heating.

Process 9

The object compound (I-n) or a salt thereof can be prepared by oxidizingthe thia moiety in R_(d) ³ of the compound (I-m) or a salt thereof.

Suitable salts of the compounds (I-m) and (I-n) can be referred to theones as exemplified for the compound (I).

This reaction can be carried out by a conventional oxidizing method usedin this field such as reacting with a suitable oxidizing agent (e.g.m-chloroperbenzoic acid, etc.).

The reduction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as benzene, hexane,dichloromethane, N,N-dimethylformamide, diethyl ether, dioxane,tetrahydrofuran, etc., or a mixture thereof.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to heating.

The compounds obtained by the above processes can be isolated andpurified by a conventional method such as pulverization,recrystallization, column chromatography, reprecipitation, or the like.

The object compound (I) can be transformed into its salt in aconventional manner.

The object compound (I) and intermediate compound (II), andpharmaceutically acceptable salts thereof have pharmacologicalactivities such as endothelin antagonistic activity (Generally, thecompound (I) has ET_(A) and ET_(B) dual antagonistic activity, and thecompound (II) has mainly ET_(A) antagonistic activity.), for example,relaxating activity of blood vessel, and the like, and useful fortherapeutical treatment and prevention of endothelin mediated diseasessuch as hypertension, heart disease such as angina pectoris,cardiomyopathy, myocardial infarction or the like, cerebral stroke suchas cerebral arterial spasm, cerebral ischemia, cerebrovascular twitch orthe like, late phase cerebral spasm after subarachnoid hemorrhage,asthma such as bronchoconstruction or the like, renal failure such asacute renal failure, renal insufficiency caused by pharmaceuticals (e.g.Cisplatin, Cyclosporins, etc.), peripheral circulatory failure, such asRaynaud's disease, Buerger's disease, etc., arteriosclerosis, diabeticnephropathy, diabetic retinopathy, shock such as hemorrhagic shock,shock induced by endotoxins, etc., hemangioendothelioma, organopathyafter re-perfusion [e.g. after organ and tissue transplantation,percutaneous transluminal coronary angiopathy (PTCA), or percutaneoustransluminal coronary recanalization (PTCR), etc.], bloodstreamdisturbance after an operation, ulcer, irritable bowel syndrome (IBS),dysuria, retinopathy, dysmenorrheal, premature birth such as prematurelabor, threatened abortion, or the like, glaucoma, re-occlusion afteroperation of PTCA, and the like.

For therapeutic purpose, the compounds (I) and (II) and pharmaceuticallyacceptable salts thereof of the present invention can be used in a formof pharmaceutical preparation containing one of said compounds, as anactive ingredient, in admixture with a pharmaceutically acceptablecarrier such as an organic or inorganic solid or liquid excipientsuitable for oral, parenteral or external (topical) administration.

The pharmaceutical preparations may be capsules, tablets, dragees,granules, solution, suspension, emulsion, sublingual tablet,suppositories, ointment, aerosol, infusion, ophthalmic solutions,vaginal suppository, and the like. If desired, there may be included inthese preparations, auxiliary substance, stabilizing agents, wetting oremulsifying agents, buffers and other commonly used additives.

While the dosage of the compounds (I) and (II) will vary depending uponthe age and condition of the patient, in the case of intravenousadministration, a daily dose of 0.01-100 mg of the active ingredient perkg weight of human being, in the case of intramuscular administration, adaily dose of 0.05-100 mg of the same per kg weight of human being, incase of oral administration, a daily dose of 0.1-100 mg of the same perkg weight of human being is generally given for the treatment ofendothelin-mediated diseases.

In order to illustrate the usefulness of the compounds (I) and (II), thepharmacological test data of a representative compound of the compounds(I) and (II) are shown in the following.

Test 1 (ET_(B) Antagonistic Activity)

Radioligand binding assay:

(1) Test Compounds

a. Compound A [The compound of Example 12-2)]

b. Compound B [The compound of Example 14-10)]

(2) Test Method

(a) Crude receptor membrane preparation:

Membranes as endothelin receptors were isolated from inner medulla ofporcine kidney. The inner medulla of porcine kidney was placed inice-cold buffer (0.25M sucrose, 5 mM Tris-HCl, 0.1 mM EDTA, pH 7.5). Theinner medulla was homogenized in five volumes (w/v) of ice-cold bufferusing a Brinkman Polytron PT-10 at a setting of 16,000 rpm for three10-sec periods. The homogenate was centrifuged at 10,000× g for 20minutes at 4° C. The pellet was discarded and the supernatant wascentrifuged at 100,000× g for 60 minutes at 4° C. The final pellet wasresuspended in three volumes of original wet weight of 50 mM Tris-HCl,pH 7.5 buffer (buffer 1) containing 100 MM NaCl, 5 mM MgCl₂, 1.5 μg/mlof (p-amidinophenyl)methanesulfonyl fluoride, 120 μg/ml of bacitracin,12 μg/ml of leupeptin, 6 μg/ml of chymostatin and 10 μg/ml ofphosphoramidon for use in the assay.

(b) ¹²⁵I-endothelin(ET)-1-binding assay:

To determine [¹²⁵I]ET-1 binding to kidney, membrane suspensions preparedfrom kidney (10 μg of protein) were incubated by constant shaking for 60minutes at 23° C. with [¹²⁵I]ET-1 (range, 4-900 pM) in a total volume of250 μl of buffer 1 that contained 0.1 mg/ml of bovine serum albumin. Inthis study, a wide range of [¹²⁵I]ET-1 concentrations was used in orderto ascertain that [¹²⁵I]ET-1 has a single class of binding sites in eachpreparation. The incubation, which was performed in duplicate, wasterminated by rapid filtration through a Whatman GF/C glass filter disk.The filter disks were washed three times with 0.1 ml of ice-cold 50 mMTris-HCl buffer (pH 7.5), and the radioactivity was counted in a gammacounter (Hewlett-Packard) with an efficiency of 71%. Nonspecific bindingwas defined as nondisplaceable binding of 3.2 μMET-1, and specificbinding was defined as the difference between total and nonspecificbinding. The K_(d) was determined by Scatchard analysis.

For determination of inhibition curves of test compounds, the membranesuspensions prepared from inner medulla of porcine kidney were incubatedwith increasing concentrations of test compounds and [¹²⁵I]ET-1 (16 pM).Specific binding represented 85% of total binding with 16 pM [¹²⁵I]ET-1in porcine kidney. Protein concentration was determined by thedye-binding assay method (Bio-Rad protein assay kit). The k_(i) forinteraction of each compound with the binding sites was calculated fromthe equation of Williams et al. (J. Biol. Chem. 251, 6915-6923, 1976).

(3) Test Results

The results are shown in Table 1.

TABLE 1 Effect on specific binding of [¹²⁵I]ET-1 in porcine kidneymembrane Test Compounds IC₅₀ (M) Compound A  7.5 × 10⁻⁸ Compound B <1.0× 10⁻⁸

Test 2 (ET_(A) Antagonistic Activity)

Radioligand binding assay:

(1) Test Compounds

a. Compound B

b. Compound C [The compound of Preparation 11-2)]

(2) Test Method

(a) Crude receptor membrane preparation:

Porcine aorta was purchased from Pel-Freez Biologicals (U.S.A.) andstored at −80° C. until use.

Porcine aorta (50 g) was thawed and dissected free from fatty tissue,minced with scissors and then homogenized with a polytron (BrinkmannPT-20, maximal speed for 3×10 sec) in 100 ml buffer (0.25M sucrose, 10mM Tris-HCl, 0.1 mM EDTA).

The homogenate was centrifuged at 10,000 g for 20 minutes at 4° C.

The supernatant, containing the plasma membrane fraction, wascentrifuged at 100,000 g for 60 minutes at 4° C., and then resultantpellets were referred to as crude membrane fractions.

The pellets were resuspended in 25 ml of binding assay buffer (50 mMTris-HCl, 100 mM NaCl, 5 mM MgCl₂, 1.5 μg/ml phenylmethylsulfonylfluoride (PMSF), 120 μg/ml bacitracin, 12 μg/ml leupepcin, 6 μg/mlchymostain, 0.1% bovine serum albumin (BSA), pH 7.5).

The aorta membrane fractions were stored at −80° C. until use.

(b) ¹²⁵I-endothelin-1 binding assay:

¹²⁵I-Endothelin-1 (1.67×10⁻¹¹ M) (Amersham Japan, specific activity:2000 Ci/m mol) was incubated with 50 μl of aorta membrane preparation inbinding assay buffer at room temperature (20-22° C.) for 60 minutes in afinal volume of 250 μl.

After incubation, the incubation mixture were filtered throughGlass-fiber GF/C filter (pretreated with 0.1% polyethylene imine for 3hours prior to use) using cell harvester (Brandel M-24S). The filterswere then washed ten times with a total of 3 ml of the washing buffer(50 mM Tris-HCl, pH 7.5) at 0° C. The filters were counted in a gammacounter (Packard Auto Gamma Model 5650).

(3) Test Results

The results are shown in Table 2.

TABLE 2 Effect on specific binding of ¹²⁵I-endothelin-1 in porcine aortamembrane Test Compounds IC₅₀ (M) Compound B 4.0 × 10⁻⁸ Compound C 5.3 ×10⁻⁷

From the results of the above-mentioned biological test, it is clearthat compound (I) has endothelin antagonistic activity, therefore areuseful for the treatment and prevention of endothelin mediated diseases,for example, hypertension, heart disease such as angina pectoris,cardiomyopathy, myocardial infarction of the like, organopathy afterreperfusion [e.g. after organ and tissue plantation, myocardialreperfusion injury, PTCA, PTCR, etc.], cerebral stroke such as cerebralarterial spasm, cerebral ischemia, cerebrovascular twitch or the like,late phase cerebral spasm after subarachnoid hemorrhage, asthma such asbronchial asthma, or the like, renal failure such as chronic or acuterenal failure renal insufficiency caused by pharmaceutical (e.g.Cisplatin, Cyclosporins, etc.), or the like.

Throughout the present specification, the amino acids, peptides,protective groups, condensing agents, etc. are indicated by theabbreviations according to the IUPAC-IUB (Commission on BiologicalNomenclature) which are in common use in a field of the art.

Moreover, other abbreviations used in this specifications are, forexample, as follows.

HCl: hydrogen chloride HPLC: High Performance Liquid ChromatographyHOBT: N-Hydroxybenzotriazole —OMe: methoxy WSCD:1-ethyl-3-(3-dimethylaminopropyl) carbodiimide Me: methyl Et: ethyl^(i)Pr: isopropyl ^(t)Bu: tert-butyl Bzl: benzyl TLC: thin layerchromatography

The following Preparations and Examples are given for the purpose ofillustrating the present invention in detail.

Preparation 1-1)

To a solution of 2-hydroxybenzaldehyde (2.44 g) in toluene (25 ml) wasadded methoxycarbonylmethylene-triphenylphosphorane (6.68 g) and themixture was stirred for 3 hours at ambient temperature. The mixture wasfiltered and the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography [eluting withethyl acetate - n-hexane (1:1)] to give methyl3-(2-hydroxyphenyl)acrylate (2.47 g).

NMR (CDCl₃, δ): 3.83 (3H, s), 6.64 (1H, d, J=16.2 Hz), 6.89-6.95 (2H,m), 7.19-7.26 (1H, m), 7.21 (1H, dd, J=7.7 and 1.6 Hz), 8.05 (1H, d,J=16.2 Hz)

Preparation 1-2)

A mixture of methyl 3-(2-hydroxyphenyl)acrylate (2.47 g) and 10%palladium on carbon (0.50 g) in methanol (30 ml) was stirred underhydrogen atmosphere for 3 hours. The mixture was filtered and thefiltrate was evaporated under reduced pressure to afford methyl3-(2-hydroxyphenyl)propionate (2.50 g).

NMR (CDCl₃, δ): 1.65 (1H, s), 2.69-2.80 (2H, m), 2.88-3.01 (2H, m), 3.69(3H, s), 6.82-6.90 (2H, m), 7.07-7.16 (2H, m)

Preparation 1-3)

To an ice-bath cooled suspension of sodium hydride (60% dispersion inmineral oil, 0.40 g) in dimethylformamide (18 ml) were added dropwisemethyl 3-(2-hydroxyphenyl)propionate (1.80 g) and benzyl bromidesuccessively. After being stirred for 30 minutes, the mixture was pouredinto a mixture of diethyl ether (20 ml) and 1N hydrochloric acidsolution (90 ml). The organic layer was separated and the aqueous layerwas extracted by diethyl ether. The combined organic layer was washedwith aqueous sodium bicarbonate solution, dried and concentrated invacuo. The residue was purified by silica gel column chromatography[eluting with ethyl acetate n-hexane (1:1)] to provide methyl3-(2-benzyloxyphenyl)-propionate (2.33 g).

NMR (CDCl₃, δ): 2.65 (2H, t, J=7.4 Hz), 3.01 (2H, t, J=7.4 Hz), 3.65(3H, s), 5.10 (2H, s), 6.86-6.93 (2H, m), 7.13-7.20 (2H, m), 7.31-7.45(5H, m)

Preparation 1-4)

To a cooled (−78° C.) solution of lithium diisopropylamide (1.55M inn-hexane) in tetrahydrofuran (2 ml) was added a solution of3-(2-benzyloxyphenyl)propionate (140 mg) in tetrahydrofuran (1.4 ml) andthe mixture was stirred for 30 minutes. Cyclohexanecarbaldehyde (80 mg)was added. After being stirred for 30 minutes at the same temperature,the mixture was quenched by 1N hydrochloric acid. The organic layer wasseparated and the aqueous layer was extracted with diethyl ether. Thecombined organic layer was washed with aqueous sodium bicarbonatesolution and brine successively, dried and evaporated under reducedpressure. The residue was purified by preparative thin layerchromatography (silica gel, 60% diethyl ether - hexane) to afford lesspolar isomer of methyl(2RS,3SR)-2-(2-benzyloxyphenylmethyl)-3-cyclohexyl-3-hydroxypropionate(isomer A) (56.2 mg) and more polar isomer of methyl(2RS,3RS)-2-(2-benzyloxyphenylmethyl)-3-cyclohexyl-3-hydroxypropionate(isomer B) (74.4 mg).

isomer A:

NMR (CDCl₃, δ): 0.80-1.80 (10H, m), 2.01 (1 H, d, J=19.9 Hz), 2.87-2.94(1H, m), 3.03-3.18 (3H, m), 3.44 (3H, s), 3.51-3.55 (1H, m), 5.07 (2H,s), 6.82-7.01 (2H, m), 7.07-7.43 (7H, m)

isomer B:

NMR (CDCl₃, δ): 0.88-1.32 (5H, m), 1.55-1.70 (5H, m), 1.87 (1H, d,J=13.2 Hz), 2.90-3.17 (3H, m), 3.29-3.42 (1H, m), 3.53 (3H, s), 5.09(2H, s), 6.82-6.92 (1H, m), 7.10-7.46 (8H, m)

Preparation 1-5)

(2RS,3RS)-2-(2-Benzyloxyphenylmethyl)-3-cyclohexyl-3-hydroxypropionicacid (711 mg) was obtained in substantially the same manner as that ofPreparation 1-6).

NMR (CDCl₃, δ): 0.75-1.62 (10H, m), 1.90 (1H, d, J=11.4 Hz), 2.93-3.26(4H, m), 5.09 (2H, s), 6.86-6.97 (2H, m), 7.13-7.44 (7H, m)

Preparation 1-6)

Methyl(2RS,3SR)-2-(2-benzyloxyphenylmethyl)-3-cyclohexyl-3-hydroxypropionate(1.14 g) was dissolved in a methanolic 1M solution of potassiumhydroxide (11 ml) and the mixture was heated under reflux for 4 hours.The solution was concentrated in vacuo and the residue was dissolved inwater and washed with diethyl ether. The aqueous layer was acidified byaqueous 1N hydrochloric acid solution and extracted with ethyl acetate.The organic layer was washed with brine, dried and evaporated underreduced pressure to give(2RS,3SR)-2-(2-benzyloxyphenylmethyl)-3-cyclohexyl-3-hydroxypropionicacid (0.998 g).

NMR (CDCl₃, δ): 0.92-1.26 (5H, m), 1.26-1.80 (5H, m), 1.90 (1H, d, J=12Hz), 2.83-3.19 (3H, m), 3.55-3.60 (1), 5.08 (2H, s), 6.82-6.98 (2H, m),7.14-7.44 (7H, m)

Preparation 2-1)

To a solution of (2-hydroxyphenyl)acetic acid (125 g) indimethylformamide (1.9 l) was added potassium carbonate (909 g) andbenzyl bromide (281 g) successively. After being stirred for 18 hours,the mixture was filtered, and the filtrate was concentrated underreduced pressure. The residue was dissolved in ethyl acetate, washedwith 1N aqueous sodium hydroxide solution and brine, dried andevaporated in vacuo. Dichloromethane was added to the residue and thesolution was treated with activated carbon. The mixture was filtered andevaporated to give benzyl (2-benzyloxyphenyl)acetate (132 g).

NMR (CDCl₃, δ): 3.73 (2H, s), 5.05 (2H, s), 5.09 (2H, s), 6.71-7.39(14H, m)

Preparation 2-2)

To a suspension of benzyl (2-benzyloxyphenyl)acetate (100 g) in ethanol(500 ml) was added a solution of sodium hydroxide (36 g) in water (300ml). After being stirred for 16 hours, the mixture was concentratedunder reduced pressure. Water was added to the residue and the mixturewas washed with diethyl ether. The aqueous layer was acidified byconcentrated-hydrochloric acid solution and extracted with ethylacetate. The organic layer was washed with brine, dried and evaporatedin vacuo. The residual oil was crystallized from diisopropyl ether toafford (2-benzyloxyphenyl)acetic acid (28 g).

NMR (CDCl₃, δ): 3.71 (2H, s), 5.07 (2H, s), 6.90-7.40 (9H, m)

Process 2-3)

To a solution of (2-benzyloxyphenyl)acetic acid (36 g) indimethylformamide (360 ml) were added potassium carbonate (61.2 g) andmethyl iodide (31.6 g) successively. After being stirred for 17 hours,the mixture was filtered and the filtrate was poured into aqueous 1Nhydrochloric acid solution (1.8 l). The separated oil was extracted withdiethyl ether and the organic layer was washed with brine, dried andevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel [eluting with ethyl acetate - n-hexane(1:1)] to afford methyl (2-benzyloxyphenyl)acetate (23 g).

NMR (CDCl₃, δ): 3.63 (3H, s), 3.69 (2H, s), 5.08 (2H, s), 6.90-7.41 (9H,m)

Preparation 2-4)

To a dry ice-acetone bath cooled solution of diisopropylamine (4.84 g)in tetrahydrofuran (100 ml) was added a 1.61M solution of n-butyllithium in n-hexane (24.8 ml) and the mixture was stirred for 30 minutesat the same temperature. Methyl (2-benzyloxyphenyl)acetate (5.12 g) wasadded and the mixture was stirred at −70° C. for 30 minutes and allowedto warm to 0° C. Cyclohexanecarbaldehyde (2.24 g) was added and thesolution was stirred for 30 minutes. The reaction mixture was quenchedby 1N aqueous hydrochloric acid solution (80 ml), washed with aqueoussodium bicarbonate solution and brine, dried, and concentrated in vacuo.The residue was purified by chromatography on silica gel (eluting with20% diethyl ether in hexane) to afford less polar isomer of methyl(2RS,3SR)-2-(2-benzyloxyphenyl)-3-cyclohexyl-3-hydroxypropionate (isomerA) (394 mg) and more polar isomer of methyl(2RS,3RS)-2-(2-benzyloxyphenyl)-3-cyclohexyl-3-hydroxypropionate (isomerB) (2.67 g).

isomer A:

NMR (CDCl₃, δ): 0.9-1.95 (11H, m), 2.46 (1H, d, J=4.3 Hz), 3.63 (3H, s),3.97-4.05 (1H, m), 4.57 (1H, d, J=5.7 Hz), 5.06 (1H, d, J=11.8 Hz), 5.13(1H, d, J=11.8 Hz), 6.94-7.01 (2H, m), 7.16-7.53 (7H, m).

isomer B:

NMR (CDCl₃, δ): 0.85-1.90 (11H, m), 3.16 (1H, d, J=5.8 Hz), 3.64 (3H,s), 3.93-3.99 (1H, m), 4.32 (1H, d, J=7.9 Hz), 5.05 (1H, d, J=11.8 Hz),5.10 (1H, d, J=11.8 Hz), 6.90-6.98 (2H, m), 7.19-7.42 (7H, m)

Preparation 2-5)

To a solution of methyl(2RS,3SR)-2-(2-benzyloxyphenyl)-3-cyclohexyl-3-hydroxypropionate (500mg) in ethanol (10 ml) was added a 1N aqueous solution of sodiumhydroxide (5 ml). After being stirred for 24 hours the mixture wasconcentrated under reduced pressure. The residue was washed with diethylether and acidified by 1N aqueous hydrochloric acid solution. Theseparated oily product was extracted by ethyl acetate. The organic layerwas washed with brine, dried and evaporated under reduced pressure toafford (2RS,3SR)-2-(2-benzyloxyphenyl)-3-cyclohexyl-3-hydroxypropionicacid (321 mg).

NMR (CDCl₃, δ): 0.90-1.40 (5H, m), 1.40-1.80 (5H, m), 1.80-2.04 (1H, m),3.99-4.05 (1H, m), 4.46 (1H, d, J=5.4 Hz), 5.06 (1H, d, J=13 Hz), 5.13(1H, d, J=12 Hz), 6.9-7.01 (2H, m), 7.20-7.56 (7H, m)

Preparation 2-6)

(2RS,3RS)-2-(2-Benzyloxyphenyl)-3-cyclohexyl-3-hydroxypropionic acid(964 mg) was obtained in substantially the same manner as that ofPreparation 2-5).

NMR (CDCl₃, δ): 0.90-1.40 (5H, m), 1.40-1.85 (6H, m), 3.98 (1H, d, J=6.4Hz), 4.31 (1H, d, J=7.8 Hz), 5.03 (1H, d, J=11.6 Hz), 5.10 (1H, d,J=11.6 Hz), 6.91-6.98 (2H, m), 7.22-7.40 (7H, m)

Preparation 3-1)

To a solution of methyl (2-benzyloxyphenyl)acetate (935 mg) intetrahydrofuran (9.4 ml) was added sodium borohydride (600 mg) and thesuspension was heated to 45° C. A mixture of methanol (3 ml) andtetrahydrofuran (6 ml) was added dropwise to the mixture and the mixturewas stirred for 2 hours. The reaction mixture was concentrated underreduced pressure. The residue was dissolved in dichloromethane andquenched by 1 N aqueous hydrochloric acid solution. The organic layerwas washed with brine, dried and evaporated under reduced pressure. Theresidue was purified by column chromatography on silica gel [elutingwith ethyl acetate - n-hexane (1:1)] to afford2-(2-benzyloxyphenyl)ethanol (764 mg).

IR (Neat): 3350, 1610, 1500, 1460, 1250, 1130, 1050, 1030 cm⁻¹

Preparation 3-2)

To an ice-water bath cooled solution of 2-(2-benzyloxyphenyl)ethanol(1.0 g) in dimethyl sulfoxide (11 ml) were added sulfur trioxidepyridine complex (2.47 g) and N,N-diisopropyl-N-ethylamine (2.0 g)successively and the mixture was stirred for 1 hour at ambienttemperature. The mixture was poured into water and extracted withdiethyl ether. The organic layer was washed with 1N aqueous hydrochloricacid solution and brine, dried, and evaporated under reduced pressure.The residue was dissolved in tetrahydrofuran (10 ml) and to the solutionwas added methoxycarbonylmethylene triphenylphosphorane (1.47 g). Afterbeing stirred for 14 hours, the mixture was concentrated under reducedpressure. The residue was purified by column chromatography on silicagel [eluting with ethyl acetate - n-hexane (1:1)] to afford methyl4-(2-benzyloxyphenyl)crotonate (0.60 g).

NMR (CDCl₃, δ): 3.57 (2H, dd, J=1.5 and 6.7 Hz), 3.71 (3H, s), 5.08 (2H,s), 5.78 (1H, dt, J=15.6 and 1.5 Hz), 6.88-7.43 (10H, m)

Preparation 3-3)

To a mixture of methyl 4-(2-benzyloxyphenyl)crotonate (14.4 g) andnickel chloride hexahydrate (1.19 g) in methanol (200 ml) was addedportionwise sodium borohydride (3.78 g). During addition, the reactiontemperature was kept at 20° C. by ice cooling. After the addition wascompleted, the mixture was stirred at ambient temperature for 1 hour andfiltered. The filtrate was concentrated under reduced pressure. To theresidue, water (100 ml) was added and the solution was extracted withdiethyl ether. The organic layer was washed with brine, dried andevaporated in vacuo and the residue was purified by columnchromatography on silica gel [eluting with ethyl acetate - n-hexane(1:1)] to give methyl 4-(2-benzyloxyphenyl)butyrate (11.5 g).

NMR (CDCl₃, δ): 1.89-2.12 (2H, m), 2.33 (2H, t, J=7.7 Hz), 2.72 (2H, t,J=7.7 Hz), 3.62 (3H, s), 5.08 (2H, s), 6.86-7.45 (9H, m)

Preparation 3-4)

To a dry ice-acetone bath cooled solution of lithium diisopropylamide,prepared from diisopropylamine (222 mg) and 1.61M hexane solution ofn-butyllithium (1.24 ml) in tetrahydrofuran (5.6 ml), was added methyl4-(2-benzyloxyphenyl)butyrate (284 mg) and the mixture was stirred for30 minutes at the same temperature. Cyclohexanecarbonyl chloride (176mg) was added. After being stirred for 30 minutes the reaction mixturewas quenched by 1N hydrochloric acid solution and the organic layer wasseparated. The aqueous layer was extracted with ethyl acetate. Thecombined organic layer was washed with aqueous sodium bicarbonatesolution and brine, and dried. The solvent was evaporated in vacuo andthe residue was purified by preparative thin layer chromatography[silica gel, ether - n-hexane (1:4)] to afford methyl4-(2-benzyloxyphenyl)-2-(cyclohexylcarbonyl)butyrate (190 mg).

NMR (CDCl₃, δ): 1.05-1.45 (5H, m), 1.57-1.80 (5H, m), 2.08-2.26 (2H, m),2.26-2.52 (1H, m), 2.68 (2H, t, J=7.2 Hz), 3.61 (1H, t, J=6.5 Hz), 3.64(3H, s), 5.07 (2H, s), 6.87-7.45 (9H, m)

Preparation 3-5)

To a solution of methyl4-(2-benzyloxyphenyl)-2-(cyclohexylcarbonyl)butyrate (1.19 g) inmethanol (50 ml) was added calcium chloride (1.11 g) and the mixture wasstirred for 30 minutes at ambient temperature. Sodium borohydride (0.20g) was added dropwise with ice cooling. After being stirred for 15minutes the mixture was poured into a mixture of ethyl acetate and 1Naqueous hydrochloric acid solution. The aqueous layer was separated andthe aqueous solution was extracted with ethyl acetate. The combinedorganic layer was washed with sodium bicarbonate solution, dried andevaporated in vacuo. The residue was purified by column chromatographyon silica gel (eluting with 1-4% diethyl ether in n-hexane) to give lesspolar isomer of methyl(2RS,3SR)-4-(2-benzyloxyphenyl)-2-[1-cyclohexyl-1-(hydroxy)methyl]-butyrate(isomer A) (1.14 g) and more polar isomer of (2RS,3RS)-isomer of thesame (isomer B) (0.10 g).

isomer A:

NMR (CDCl₃, δ): 0.80-1.80 (11H, m), 1.91-2.06 (2H, m), 2.30 (1H, d,J=4.2 Hz), 2.55-2.83 (2H, m), 3.49-3.56 (1H, m), 3.63 (3H, s), 5.10 (2H,s), 6.86-7.46 (9H, m)

isomer B:

NMR (CDCl₃, δ): 0.80-1.80 (11H, m), 1.80-2.10 (2H, m), 2.45 (1H, d,J=8.7 Hz), 2.60-2.72 (2H, m), 3.36-3.43 (1H, m), 3.64 (3H, s), 5.08 (2H,s), 6.86-7.46 (9H, m)

Preparation 3-6)

To a solution of methyl4-(2-benzyloxyphenyl)-2-(cyclohexylcarbonyl)butyrate (2.8 g) in methanol(28 ml) was added tetrabutylammonium borohydride (2.2 g) with icecooling. After being stirred for 1.5 hours at the same temperature, thereaction mixture was quenched by 1N aqueous hydrochloric acid solution,and extracted with ethyl acetate. The organic layer was washed withaqueous sodium bicarbonate solution, dried and evaporated under reducedpressure to afford a mixture of diastereoisomers of methyl (2RS,3RS)-and(2RS,3SR)-4-(2-benzyloxyphenyl)-2-[1-cyclohexyl-1-(hydroxy)methyl]butyrate(2.9 g) ((2RS,3RS):(2RS,3SR)=3.37:1). Purification of the products bycolumn chromatography on silica gel (eluting with ethyl acetate -n-hexane (1:1) provided pure (2RS,3RS)-isomer of the same (712 mg).

(2RS,3RS)-isomer:

NMR (CDCl₃, δ): 0.80-1.80 (11H, m), 1.80-2.10 (2H, m), 2.45 (1H, d,J=8.7 Hz), 2.60-2.72 (2H, m), 3.36-3.43 (1H, m), 3.64 (3H, s), 5.08 (2H,s), 6.86-7.46 (9H, m)

Preparation 3-7)

(2RS,3SR)-4-(2-Benzyloxyphenyl)-2-[1-cyclohexyl-1-(hydroxy)methyl]butyricacid (1.05 g) was obtained in substantially the same manner as that ofPreparation 2-5).

NMR (CDCl₃, δ): 0.80-1.80 (11H, m), 1.80-2.10 (2H, m), 2.61-2.86 (3H,m), 3.55-3.65 (1H, m), 5.07 (2H, s), 6.86-7.45 (9H, m)

Preparation 3-8)

(2RS,3RS)-4-(2-Benzyloxyphenyl)-2-(1-cyclohexyl-1-(hydroxy)methyl]butyricacid (563 mg) was obtained in substantially the same manner as that ofPreparation 3-7).

NMR (CDCl₃, δ): 0.80-1.82 (11H, m), 1.92-2.08 (2H, m), 2.60-2.78 (3H,m), 3.41-3.47 (1H, m), 5.06 (2H, s), 6.84-7.47 (9H, m)

Preparation 4-1)

Methyl-3-(2-methoxyphenyl)propionate (5.01 g) was obtained from methyl3-(2-hydroxyphenyl)propionate (4.95 g) and methyl iodide (3.9 g) insubstantially the same manner as that of Preparation 2-1).

NMR (CDCl₃, δ): 2.61 (2H, q, J=7.4 and 11.2 Hz), 2.93 (2H, q, J=7.4 and11.2 Hz), 3.66 (3H, s), 3.82 (3H, s), 6.82-6.91 (2H, m), 7.12-7.25 (2H,m)

Preparation 4-2)

Methyl 3-(2-methoxyphenyl)propionate (1.80 g) was reacted withcyclohexane carbaldehyde (1.25 g) in substantially the same manner asthat of Preparation 1-4) to give less polar isomer of methyl(2RS,3SR)-3-cyclohexyl-3-hydroxy-2-(2-methoxyphenylmethyl)propionate(isomer A) (0.706 g) and more polar isomer of (2RS,3RS)-isomer of thesame (isomer B) (0.940 g).

isomer A:

NMR (CDCl₃, δ): 0.95-1.78 (10 H, m), 2.04 (1H, d, J=12.7 Hz), 2.64-3.14(4H, m), 3.51 (3H, s), 3.57-3.61 (1H, m), 3.87 (3H, s), 6.81-6.88 (2H,m), 7.05-7.23 (2H, m)

isomer B:

NMR (CDCl₃, δ): 0.95-1.82 (10H, m), 1.96 (1H, d, J=13.4 Hz), 2.66 (1H,d, J=9.0 Hz), 2.93-3.01 (3H, m), 3.20-3.38 (1H, m), 3.57 (3H, s), 3.94(3H, s), 6.82-6.90 (2H, m), 7.08-7.25 (2H, m)

Preparation 4-3)

(2RS,3SR)-3-Cyclohexyl-3-hydroxy-2-(2-methoxyphenyl-methyl)propionicacid (340 mg) was obtained in substantially the same manner as that ofPreparation 1-6).

NMR (CDCl₃, δ): 0.85-1.40 (5H, m), 1.40-1.85 (5H, m), 2.03 (1H, d,J=12.4 Hz), 2.83-3.10 (3H, m), 3.64 (1H, dd, J=3.3 and 7.4 Hz), 3.79(3H, s), 6.81-6.89 (2H, m), 7.12-7.25 (2H, m)

Preparation 5-1)

To a suspension of (t-butoxycarbonylmethyl)-triphenylphosphoniumchloride (20.7 g) in tetrahydrofuran (200 ml) was added potassiumt-butoxide (5.60 g) portionwise and the mixture was stirred for 30minutes at ambient temperature. 2-Carboxybenzaldehyde was added to themixture. After being stirred for 1 hour the reaction mixture wasfiltered and the filtrate was evaporated under reduced pressure. Theresidue was dissolved in 1N aqueous sodium hydroxide solution and washedwith ethyl acetate. The aqueous layer was acidified by conc.hydrochloric acid solution and extracted with ethyl acetate. The organiclayer was washed with brine, dried and concentrated under reducedpressure to afford t-butyl 3-(2-carboxyphenyl)acrylate (8.3 g).

NMR (CDCl₃, δ): 1.55 (9H, s), 6.27 (1H, d, J=15.9 Hz), 7.26-7.65 (3H,m), 8.09 (1H, dd, J=0.8 and 7.5 Hz), 8.47 (1H, d, J=15.9 Hz)

Preparation 5-2)

t-Butyl 3-(2-carboxyphenyl)propionate was obtained in substantially thesame manner as that of Preparation 1-2).

NMR (CDCl₃, δ): 1.42 (9H, s), 2.58-2.83 (2H, m), 3.24-3.50 (2H, m),7.26-7.53 (3H, m), 8.04-8.11 (1H, m)

Preparation 5-3)

A diastereisomeric mixture of t-butyl2-(2-carboxyphenylmethyl)-3-cyclohexyl-3-hydroxypropionate (1.4 g) wasobtained in substantially the same manner as that of Preparation 1-4).

NMR (CDCl₃, δ): 0.80-1.50 (5H, m), 1.21 (4.5H, s), 1.29 (4.5H, s),1.35-1.85 (5H, m), 1.85-2.10 (1H, m), 3.01-3.70 (4H, m), 7.25-7.49 (3H,m), 8.06 (1H, d, J=7.5 Hz)

Preparation 5-4)

To a solution of t-butyl2-(2-carboxyphenylmethyl)-3-cyclohexyl-3-hydroxypropionate (200 mg) indimethylformamide (2 ml) were added benzyl bromide (100 mg) andpotassium carbonate (270 mg) successively. After being stirred for 30minutes the mixture was filtered and the filtrate was evaporated underreduced pressure. The residue was purified by preparative thin layerchromatography [silica gel, ethyl acetate - n-hexane (1:1)] to affordt-butyl2-(2-benzyloxycarbonylphenylmethyl)-3-cyclohexyl-3-hydroxypropionate(108 mg).

NMR (CDCl₃, δ): 0.80-1.25 (5H, m), 1.20 (4.5H, s), 1.25 (4.5H, s),1.50-1.80 (5H, m), 1.80-2.07 (1H, m), 2.81-3.75 (4H, m), 5.28-5.41 (2H,m), 7.22-7.46 (8H, m), 7.96 (1H, d, J=7.3 Hz)

Preparation 5-5)

t-Butyl2-(2-benzyloxycarbonylphenylmethyl)-3-cyclohexyl-3-hydroxypropionate(100 mg) was dissolved in a solution of 10% trifluoroacetic acid indichloromethane (1 ml) and the mixture was stirred for 5 hours. Thesolution was evaporated under reduced pressure and the residue waspurified by chromatography [eluting with methanol-dichloromethane(1:19)] to give2-(2-benzyloxycarbonyl-phenylmethyl)-3-cyclohexyl-3-hydroxypropionicacid (35 mg).

NMR (CDCl₃, δ): 0.75-2.10 (11H, m), 2.95-3.30 (2H, m), 3.47-3.66 (1H,m), 5.32 and 5.35 (2H, each s), 7.26-7.42 (8H, m), 7.92 (1H, d, J=7.7Hz)

Preparation 6-1)

To a solution of(2RS,3RS)-2-(2-benzyloxyphenyl)-3-cyclohexyl-3-hydroxypropionic acid(354 mg) in dichloromethane (7 ml) was added hydroquinine (326 mg) andthe mixture was stirred to be a clear solution. The solvent wasevaporated under reduced pressure and the residue was crystallized fromethyl acetate. Precipitates were recrystallized from a mixture of ethylacetate and ethanol (50:1) to afford hydroquinine salt of(2S,3S)-2-(2-benzyloxyphenyl)-3-cyclohexyl-3-hydroxypropionic acid ascrystals (150 mg).

NMR (CDCl₃, δ): 0.75 (3H, t, J=7.0 Hz), 0.90-1.30 10H, m), 1.45-1.80(8H, m), 1.80-2.05 (3H, m), 2.45-2.60 (1H, m), 2.70-2.90 (1H, m),3.10-3.30 (2H, m), 3.52 (3H, s), 3.83-3.87 (1H, m), 4.00-4.20 (2H, m),4.82 (1H, d, J=11.7 Hz), 4.96 (1H, d, J=11.7 Hz), 6.03 (1H, s),6.80-6.89 (2H, m), 7.08-7.49 (9H, m), 7.86 (1H, d, J=9.2 Hz), 8.62 (1H,d, J=4.5 Hz)

[α]_(D) ²¹: −46.6° (C=1.0, CH₂Cl₂)

Mother liquid of the recrystallization was evaporated under reducedpressure to give hydroquinine salt of (2R,3R)-isomer of the same as amain component in an oily form.

NMR (CDCl₃, δ): 0.75 (3H, t, J=7.0 Hz), 0.95-1.30 (10H, m), 1.45-1.80(8H, m), 1.80-2.10 (3H, m), 2.45-2.60 (1H, m), 2.85-2.95 (1H, m),3.10-3.20 (1H, m), 3.34 (3H, s), 3.65-3.70 (1H, m), 4.83-5.09 (2H, m),6.05 (1H, s), 6.67 (1H, d, J=2.5 Hz), 6.82-7.48 (10H, m), 7.75 (1H, d,J=9.2 Hz), 8.52 (1H, d, J=4.5 Hz)

[α]_(D) ²¹: −17.6° (C=1.0, CH₂Cl₂)

Preparation 6-2)

The hydroquinine salt of(2S,3S)-2-(2-benzyloxyphenyl)-3-cyclohexyl-3-hydroxypropionic acid (40mg) was suspended in ethyl acetate and washed with 1N aqueoushydrochloric acid solution. The organic layer was washed with brine,dried and evaporated under reduced pressure to give(2S,3S)-2-(2-benzyloxyphenylmethyl)-2-carboxy-2-hydroxypropionic acid(21 mg).

[α]_(D) ²¹: −64.3° (C=1.2, CH₂Cl₂)

The hydroquinine salt of(2R,3R)-2-(2-benzyloxyphenylmethyl)-3-cyclohexyl-3-hydroxypropionic acid(40 mg) obtained in Preparation 6-1) was dissolved in ethyl acetate. Thesolution was washed with 1N aqueous hydrochloric acid solution andbrine, dried, and evaporated in vacuo to afford a product which contains(2R,3R)-2-(2-benzyloxyphenylmethyl)-3-cyclohexyl-3-hydroxypropionic acidas a main isomer (20 mg).

[α]_(D) ²¹: 22.2° (C=1.0, CH₂Cl₂)

Preparation 7

To a dry ice-acetone bath cooled 1.45M solution of lithiumdiisopropylamide in a mixture of tetrahydrofuran and n-hexane (1.4 ml)was added methyl (2-benzyloxyphenyl)acetate (256 mg). The mixture wasstirred for 30 minutes at the same temperature and then for 30 minutesat 0° C. After cooling the solution to −78° C. chlorotrimethylsilane(0.3 ml) was added and the mixture was allowed to warm to roomtemperature. The solution was diluted with n-hexane (50 ml), filteredthrough celite, and concentrated under reduced pressure to afford2-(2-benzyloxyphenyl)-1-methoxy-1-trimethylsilyloxyethylene. To an icebath cooled solution of (2S)-3-methyl-2-(p-tolylsulfonylamino)butanol(288 mg) in dichloromethane (10 ml) was added a 1M solution ofborane-tetrahydrofuran complex in tetrahydrofuran (1.0 ml) and themixture was stirred for 30 minutes at ambient temperature. After coolingthe solution to −78° C., cyclohexanecarbaldehyde (112 mg) and a solutionof 2-(2-benzyloxyphenyl)-1-methoxy-1-trimethylsilyloxyethylene preparedabove in dichloromethane (1 ml) were added. The solution was stirred forone hour at −78° C. and then quenched by an aqueous solution of sodiumbicarbonate at 0° C. The mixture was extracted with diethyl ether, driedand evaporated in vacuo. The residue was dissolved in a mixture oftetrahydrofuran (4 ml) and aqueous 1M solution of hydrochloric acid (2ml), and the resulting solution was allowed to stand for 30 minutes.Aqueous solution of sodium bicarbonate was added thereto and the mixturewas extracted with ether. The organic layer was dried and evaporated.Preparative thin layer chromatography [silica gel, ether - hexane (1:4)]afforded methyl(2R,3R)-2-(2-benzyloxyphenyl)-3-cyclohexyl-3-hydroxypropionate (187 mg).High pressure liquid chromatography analysis (Daicel AD column elutingwith 20% isopropyl alcohol - hexane) indicated an enantiomeric excess of95% (Rt: major 10.51 minutes, minor 8.60 minutes).

NMR (CDCl₃, δ): 0.85-1.90 (11H, m), 3.16 (1H, d, J=5.8 Hz), 3.64 (3H,s), 3.93-3.99 (1H, m), 4.32 (1H, d, J=7.9 Hz), 5.05 (1H, d, J=11.8 Hz),5.10 (1H, d, J=11.8 Hz), 6.90-6.98 (2H, m), 7.19-7.42 (7H, m)

Preparation 8-1)

To a solution of 3,4-methylenedioxyphenylacetic acid (10 g) in ethanol(100 ml) was added conc. sulfuric acid (3 ml). After being refluxed for90 minutes, the mixture was concentrated in vacuo. The residue wasdissolved in diethyl ether (150 ml). The solution was washed with 1Maqueous sodium bicarbonate solution and brine successively and driedover magnesium sulfate, and concentrated in vacuo to give ethyl3,4-methylenedioxyphenylacetate (11.0 g) as an oil.

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 3.52 (2H, s), 4.15 (2H, q, J=7Hz), 5.94 (2H, s), 6.70-6.82 (3H, m)

Preparation 8-2)

To a solution of N,N-diisopropyl-N-ethylamine (4.49 g) intetrahydrofuran (50 ml) was added with stirring 1.6M n-butyl lithium inn-hexane solution (27.6 ml) below 0° C. under a nitrogen atmosphere.After the mixture was stirred in an ice-bath for 30 minutes, a solutionof ethyl 3,4-methylenedioxyphenylacetate (3.85 g) in tetrahydrofuran (40ml) was added at −78° C. The mixture was stirred for 30 minutes andcyclohexanecarbaldehyde (2.49 g) was added. After being stirred for 15minutes at the same temperature, the mixture was quenched by saturatedaqueous ammonium acetate. The mixture was extracted with diethyl ether(100 ml), and the solution was washed with 1M hydrochloric acid andbrine successively, dried over magnesium sulfate and concentrated invacuo. The residue was purified by silica gel column chromatography(eluent; n-hexane:ethyl acetate=6:1) to give ethyl(2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-cyclohexyl-3-hydroxypropionate(4.45 g) as an oil.

NMR (CDCl₃, δ): 0.92-1.80 (14H, m), 2.55 (1H, d, J=6.5 Hz), 3.62-3.70(1H, m), 3.85-3.95 (1H, m), 4.02-4.22 (2H, m), 5.94 (1H, s), 6.75 (2H,s), 6.80 (1H, s)

FAB MS m/z: 321 [M+H]⁺

Preparation 8-3)

To a solution of ethyl(2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-cyclohexyl-3-hydroxypropionate(4.2 g) in ethanol (50 ml) was added 1M sodium hydroxide solution (26.2ml) at room temperature. After being stirred for 1.5 hours at the sametemperature, the mixture was concentrated in vacuo. The residue wasdissolved in 1N hydrochloric acid (50 ml) and ethyl acetate (100 ml) andthe organic layer was washed with brine, dried over magnesium sulfate,and concentrated in vacuo. The residue was crystallized from n-hexane togive(2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-cyclohexyl-3-hydroxypropionicacid (1.43 g).

mp: 162-163° C.

NMR (CDCl₃, δ): 0.96-1.76 (11H, m), 3.72 (1H, d, J=8 Hz), 3.94 (1H, d,J=8 Hz), 5.93 (1H, s), 6.75 (2H, s), 6.82 (1H, s)

FAB MS m/z: 293 [M+H]⁺

Preparation 9

Ethyl (2-methoxyphenyl)acetic acid (11.1 g) was obtained insubstantially the same manner as that of Preparation 8-1).

This product was immediately used for the next step.

Preparation 9-2)

Ethyl (2RS,3RS)-2-(2-methoxyphenyl)-3-cyclohexyl-3-hydroxypropionate(2.56 g) was obtained in substantially the same manner as that ofPreparation 8-2).

NMR (CDCl₃, δ): 0.96-1.41 (6H, m), 1.18 (3H, t, J=8 Hz), 1.48-1.90 (5H,m), 3.20 (1H, d, J=7 Hz), 3.82 (3H, s), 3.86-3.95 (1H, m), 4.10-4.20(2H, m), 4.22 (1H, d, J=8 Hz), 6.88 (1H, d, J=8 Hz), 9.64 (1H, d, J=8Hz), 7.20-7.32 (2H, m)

FAB MS m/z: 307 [M+H]⁺

Preparation 9-3)

(2RS,3RS)-2-(2-Methoxyphenyl)-3-cyclohexyl-3-hydroxypropionic acid (1.34g) was obtained in substantially the same manner as that of Preparation8-3).

mp: 99-101° C.

NMR (CDCl₃, δ): 0.98-1.38 (6H, m), 1.48-1.85 (5H, m), 3.82 (1H, s), 3.94(1H, m), 4.28 (1H, d, J=7 Hz), 7.86-7.96 (2H, m), 7.18-7.30 (2H, m)

FAB MS m/z: 279 [M+H]⁺

The following compounds were obtained in substantially the same manneras that of Preparation 8-2).

Preparation 10-1)

Ethyl (2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-hydroxyheptanoate (370mg)

NMR (CDCl₃, δ): 0.84 (3H, t, J=7 Hz), 1.21 (3H, t, J=7 Hz), 1.20-1.55(6H, m), 2.70 (1H, d, J=6.5 Hz), 3.45 (1H, d, J=8 Hz), 4.00-4.25 (3H,m), 5.95 (2H, s), 6.70-6.82 (3H, m)

FAB MS m/z: 295 [M+H]⁺

Preparation 10-2)

Ethyl (2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-hydroxyhexanoate (350 mg)

NMR (CDCl₃, δ): 0.84 (3H, t, J=8 Hz), 1.22 (3H, t, J=7 Hz), 1.24-1.60(4H, m), 3.45 (1H, d, J=8 Hz), 4.02-4.22 (3H, m), 5.95 (2H, s),6.70-6.80 (3H, m)

FAB MS m/z: 281 [M+H]⁺

Preparation 10-3)

Ethyl (2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-hydroxyoctanoate (415 mg)

NMR (CDCl₃, δ): 0.84 (3H, t, J=8 Hz), 1.14-1.55 (8H, m), 2.70 (1H, d,J=7 Hz), 3.45 (1H, d, J=8 Hz), 4.02-4.28 (3H, m), 5.95 (2H, s),6.70-6.82 (3H, m)

FAB MS m/z: 309 [M+H]⁺

Preparation 10-4)

Ethyl (2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-hydroxy-4-ethylhexanoate(677 mg)

NMR (CDCl₃, δ): 0.80-1.02 (7H, m), 1.15-1.60 (7H, m), 2.45 (1H, d, J=7Hz), 3.70 (1H, d, J=8 Hz), 4.05-4.28 (3H, m), 5.95 (2H, s), 6.70-6.85(3H, m)

FAB MS m/z: 309 [M+H]⁺

Preparation 10-5)

Ethyl (2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-hydroxy-5-methylhexanoate(339 mg)

NMR (CDCl₃, δ): 0.88-0.90 (6H, m), 0.90-1.06 (1H, m), 1.18-1.37 (4H, m),1.76-1.90 (1H, m), 2.64 (1H, d, J=6 Hz), 3.40 (1H, d, J=8 Hz), 4.02-4.22(3H, m), 5.95 (2H, s), 6.68-6.80 (3H, m)

FAB MS m/z: 295 [M+H]⁺

Preparation 10-6)

Ethyl(2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-hydroxy-4-cyclohexylbutyrate(352 mg)

NMR (CDCl₃, δ): 0.60-1.80 (16H, m), 2.64 (1H, d, J=6 Hz), 3.40 (1H, d,J=8 Hz), 4.05-4.25 (3H, m), 5.94 (2H, s), 6.65-6.80 (3H, m)

FAB MS m/z: 335 [M+H]⁺

Preparation 10-7)

Ethyl (2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-hydroxyvalerate (555 mg)

NMR (CDCl₃, δ): 0.92 (3H, t, J=7 Hz), 1.22 (3H, t, J=8 Hz), 1.25-1.50(2H, m), 2.19 (1H, d, J=6 Hz), 3.48 (1H, d, J=8 Hz), 3.95-4.25 (3H, m),5.95 (2H, s), 6.70-6.80 (3H, m)

FAB MS m/z: 267 [M+H]⁺

Preparation 10-8)

Ethyl(2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-hydroxy-5,5-dimethylhexanoate(930 mg)

NMR (CDCl₃, δ): 0.87 (9H, s), 1.21 (3H, t, J=7 Hz), 1.20-1.33 (2H, m),2.57 (1H, d, J=7 Hz), 3.40 (1H, d, J=8 Hz), 4.02-4.25 (3H, m), 5.95 (2H,s), 6.70-6.80 (3H, m)

FAB MS m/z: 309 [M+H]⁺

Preparation 10-9)

Ethyl (2RS,3RS)- and(2RS,3SR)-3-hydroxy-4-methyl-2-(3,4-methylenedioxyphenyl)valerate wasobtained in substantially the same manner as that of Preparation 8-2).

The stereoisomers were separated by silica gel column chromatography (30g)(eluent; n-hexane:ethyl acetate=9:1) to give more polar isomer (1.02g) and less polar isomer (330 mg). The stereostructures of the morepolar and the less polar isomers were assigned as (2RS,3RS)- and(2RS,3SR)-configurations respectively.

More polar isomer:

NMR (CDCl₃, δ): 0.87 (3H, d, J=8 Hz), 0.96 (3H, d, J=8 Hz), 1.22 (3H, t,J=8 Hz), 1.44-1.53 (1H, m), 2.50 (1H, d, J=7 Hz), 3.61 (1H, d, J=10 Hz),3.93-4.00 (1H, m), 4.06-4.22 (2H, m), 5.95 (2H, s), 6.76 (2H, s), 6.82(1H, s)

Less polar isomer:

NMR (CDCl₃, δ): 0.98 (3H, d, J=4 Hz), 1.00 (3H, d, J=4 Hz), 1.02 (3H, t,J=8 Hz), 1.59-1.70 (1H, m), 2.26 (1H, d, J=4 Hz), 3.62 (1H, d, J=8 Hz),3.87-3.94 (1H, m), 4.06-4.21 (2H, m), 5.95 (2H, s), 6.77 (1H, d, J=9Hz), 6.85 (1H, d, J=9 Hz), 6.99 (1H, s)

The following compounds were obtained in substantially the same manneras that of Preparation 8-2).

Preparation 10-10)

Benzyl 3-hydroxy-2-(3,4-methylenedioxyphenyl)-3-phenylpropionate (1.16g)

NMR (CDCl₃, δ): 2.40 (0.3H, d, J=1 Hz), 2.99 (0.7H, d, J=3 Hz),3.82-3.86 (1H, m), 4.84-5.26 (3H, m), 5.88-5.95 (2H, m), 6.48-7.03 (3H,m), 7.10-7.34 (10H, m)

Preparation 10-11)

Benzyl 3-hydroxy-2-(3,4-methylenedioxybenzyl)-3-phenylpropionate (2.88g)

NMR (CDCl₃, δ): 2.65-3.10 (4H, m), 4.81-5.05 (3H, m), 5.89, 5.90 (total2H, s), 6.49-6.68 (3H, m), 6.96-7.06 (2H, m), 7.25-7.39 (8H, m)

Preparation 10-12)

Ethyl (2RS)-2-(3,4-methylenedioxyphenyl)-3-phenylpropionate

NMR (CDCl₃, δ): 1.13 (3H, t, J=8 Hz), 2.98 (1H, dd, J=7, 14 Hz), 3.34(1H, dd, J=9, 14 Hz), 3.74 (1H, dd, J=7, 9 Hz), 4.00-4.12 (2H, m), 5.95(2H, s), 6.74 (2H, s), 6.88 (1H, s), 7.10-7.17 (2H, m), 7.18-7.28 (3H,m)

FAB MS: 298.3 [M]⁺

The following compounds were obtained in substantially the same manneras that of Preparation 8-3).

Preparation 11-1)

(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyheptanoic acid (300 mg)

mp: 107-108° C.

NMR (CDCl₃, δ): 0.84 (3H, t, J=8 Hz), 1.16-1.55 (6H, m), 3.50 (1H, d,J=8 Hz), 4.10 (1H, m), 5.95 (2H, s), 6.70-6.85 (3H, m)

FAB MS m/z: 267 [M+H]⁺

Preparation 11-2)

(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyhexanoic acid (174 mg)

mp: 138-139° C.

NMR (CDCl₃, δ): 0.85 (3H, t, J=8 Hz), 1.29 (3H, m), 1.42-1.60 (1H, m),3.50 (1H, d, J=8 Hz), 4.05-4.20 (1H, m), 5.96 (2H, s), 6.70-6.88 (3H, m)

FAB MS m/z: 253 [M+H]⁺

Preparation 11-3)

(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyoctanoic acid (300 mg)

mp: 121-122° C.

NMR (CDCl₃, δ): 0.84 (3H, t, J=8 Hz), 1.10-1.55 (8H, m), 3.50 (1H, d,J=8 Hz), 4.05-4.15 (1H, m), 5.96 (2H, s), 6.70-6.85 (3H, m)

FAB MS m/z: 281 [M+H]⁺

Preparation 11-4)

(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxy-4-ethylhexanoic acid(330 mg)

mp: 155-156° C.

NMR (CDCl₃, δ): 0.82 (6H, t, J=7 Hz), 0.90-1.00 (1H, m), 1.13-1.58 (4H,m), 3.74 (1H, d, J=8 Hz), 4.22 (1H, dd, J=3, 8 Hz), 5.97 (2H, s),6.72-6.80 (2H, m), 6.82 (1H, s)

FAB MS m/z: 281 [M+H]⁺

Preparation 11-5)

(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxy-5-methylhexanoic acid(229 mg)

mp: 141-143° C.

NMR (CDCl₃, δ): 0.78-0.90 (6H, m), 0.95-1.08 (1H, m), 1.18-1.37 (1H, m),1.73-1.90 (1H, m), 3.46 (1H, d, J=8 Hz), 4.10-4.19 (1H, m), 5.95 (2H,s), 6.70-6.90 (3H, m)

FAB MS m/z: 267 [M+H]⁺

Preparation 11-6)

(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxy-4-cyclohexylbutyricacid (175 mg)

mp: 171° C.

NMR (CDCl₃, δ): 0.60-1.80 (13H, m), 3.45 (1H, d, J=9 Hz), 4.15-4.25 (1H,m), 5.94 (2H, s), 6.70-6.80 (3H, m)

FAB MS m/z: 307 [M+H]⁺

Preparation 11-7

(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyvaleric acid (362 mg)

mp: 124-126° C.

NMR (CDCl₃, δ): 0.92 (3H, t, J=8 Hz), 1.20-1.50 (2H, m), 3.50 (1H, d,J=8 Hz), 4.00-4.10 (1H, m), 5.95 (2H, s), 6.70-6.80 (3H, m)

FAB MS m/z: 239 [M+H]⁺

Preparation 11-8)

(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxy-5,5-dimethylhexanoicacid (320 mg)

mp: 186-187° C.

NMR (CDCl₃, δ): 0.87 (9H, s), 1.27 (2H, t, J=8 Hz), 3.48 (1H, d, J=8Hz), 4.15-4.25 (1H, m), 5.95 (2H, s), 6.70-6.80 (3H, m)

FAB MS m/z: 279 [M−H]⁻

Preparation 11-9)

(2RS,3RS)-3-Hydroxy-4-methyl-2-(3,4-methylenedioxyphenyl)valeric acid(710 mg)

mp: 105-110° C.

NMR (DMSO-d₆, δ): 0.68 (3H, d, J=8 Hz), 0.81 (3H, d, J=8 Hz), 3.40 (1H,d, J=10 Hz), 3.88 (1H, dd, J=1, 10 Hz), 5.98 (2H, s), 6.78 (1H, d, J=8Hz), 6.84 (1H, d, J=8 Hz), 6.90 (1H, s)

FAB MS: 252 [M+H]⁺

Preparation 11-10)

(2RS,3SR)- and(2RS,3RS)-3-Hydroxy-2-(3,4-methylenedioxyphenyl)-3-phenylpropionic acidwas obtained in substantially the same manner as that of Preparation14-1).

The stereoisomers were separated by silica gel column chromatography(eluent; n-hexane:ethyl acetate=2:1) to give more polar isomer (220 mg)and less polar isomer (164 mg). The stereostructures of the more polarand the less polar isomers were assigned as (2RS,3SR)- and(2RS,3RS)-configurations respectively.

More polar isomer:

NMR (CDCl₃, δ): 3.84 (1H, d, J=9 Hz), 5.12 (1H, d, J=9 Hz), 5.88 (2H, d,J=5 Hz), 6.53 (1H, dd, J=1, 8 Hz), 6.60 (1H, d, J=8 Hz), 6.69 (1H, d,J=1 Hz), 7.12-7.17 (2H, m), 7.18-7.25 (3H, m)

FAB MS: 269.2 [M−OH]⁺

Less polar isomer:

mp: 145-148° C.

NMR (CDCl₃, δ): 3.80 (1H, d, J=8 Hz), 5.22 (1H, d,

J=8 Hz), 5.96 (2H, s), 6.76 (2H, s), 6.92 (1H, s), 7.25-7.34 (5H, m)

FAB MS: 269.1 [M−OH]⁺

Preparation 11-11)

(2RS,3SR)- and(2RS,3RS)-3-Hydroxy-2-(3,4-methylenedioxybenzyl)-3-phenylpropionic acidwas obtained in substantially the same manner as that of Preparation14-1).

The stereoisomers were separated by silica gel column chromatography(eluent; n-hexane:ethyl acetate=3:2) to give more polar isomer (335 mg)and less polar isomer (615 mg). The stereostructures of the more polarand the less polar isomers were assigned as (2RS,3SR)- and(2RS,3RS)-configurations respectively.

More polar isomer:

mp: 130-133° C.

NMR (DMSO-d₆, δ): 2.20 (1H, dd, J=4, 14 Hz), 2.54 (1H, d, J=14 Hz),2.74-2.81 (1H, m), 4.63 (1H, d, J=8 Hz), 5.93 (2H, s), 6.47 (1H, dd,J=1, 8 Hz), 6.57 (1H, d, J=1 Hz), 6.73 (1H, d, J=8 Hz), 7.22-7.40 (5H,m)

FAB MS: 300 [M]⁺

Less polar isomer:

NMR (DMSO-d₆, δ): 2.70-2.82 (2H, m), 2.93-3.03 (1H, m), 4.65 (1H, d, J=8Hz), 5.93 (2H, s), 6.57 (1H, d, J=8 Hz), 6.66 (1H, d, J=1 Hz), 6.76 (1H,d, J=8 Hz), 7.19-7.37 (5H, m)

FAB MS: 300 [M]⁺

Preparation 11-12)

(2RS)-2-(3,4-Methylenedioxyphenyl)-3-phenylpropionic acid (422 mg) wasobtained in substantially the same manner as that of Preparation 8-3).

NMR (CDCl₃, δ): 3.00 (1H, dd, J=7, 14 Hz), 3.35 (1H, dd, J=9, 14 Hz),3.78 (1H, dd, J=7, 9 Hz), 5.95 (2H, t, J=1 Hz), 6.73 (2H, s), 6.86 (1H,s), 7.07-7.13 (2H, m), 7.17-7.28 (3H, m)

FAB MS: 270.2 [M]⁺

Preparation 12-1)

To a solution of 1,4-benzodioxane-6-acetic acid (5.0 g) and potassiumcarbonate (2.13 g) in dimethylformamide (20 ml) was added benzyl bromide(4.84 g) at room temperature. After being stirred at the sametemperature for 3 hours, the mixture was poured into water (200 ml) andextracted with diethyl ether (150 ml). The organic layer was washed with5% hydrochloric acid solution, 1M aqueous sodium bicarbonate solutionand brine, dried over magnesium sulfate, and concentrated in vacuo toafford benzyl 1,4-benzodioxane-6-acetate (7.08 g) as an oil.

NMR (CDCl₃, δ): 3.54 (2H, s), 4.22 (4H, s), 5.10 (2H, s), 6.70-6.82 (3H,m), 7.28-7.40 (5H, m)

The following compounds were obtained in substantially the same manneras that of Preparation 12-1).

Preparation 12-2)

Benzyl 2-naphthylacetate (5.38 g)

This product was immediately used for the next step.

Preparation 12-3)

Benzyl 3,4-dimethoxyphenylacetate (6.80 g)

This product was immediately used for the next step.

The following compounds were obtained in substantially the same manneras that of Preparation 8-2).

Preparation 13-1)

Benzyl (2RS,3RS)-2-(1,4-benzodioxan-6-yl)-3-hydroxyheptanoate (742 mg)

NMR (CDCl₃, δ): 0.78-0.90 (3H, m), 1.20-1.52 (6H, m), 3.46-3.52 (1H, m),4.06-4.20 (1H, m), 4.24 (4H, s), 5.02-5.23 (2H, m), 6.70-6.92 (3H, m),7.20-7.40 (5H, m)

FAB MS m/z: 371 [M+H]⁺

Preparation 13-2)

Benzyl (2RS,3RS)-2-(2-naphthyl)-3-hydroxyheptanoate (742 mg)

NMR (CDCl₃, δ): 0.78 (3H, t, J=7 Hz), 1.10-1.52 (6H, m), 2.74 (1H, d,J=7 Hz), 3.30 (1H, d, J=8 Hz), 4.22-4.35 (1H, m), 5.08 (1H, d, J=11 Hz),5.20 (1H, d, J=11 Hz), 7.15-7.28 (5H, m), 7.35-7.51 (3H, m), 7.70-7.88(4H, m)

FAB MS m/z: 363 [M+H]⁺

Preparation 13-3)

Benzyl (2RS,3RS)-2-(3,4-dimethoxyphenyl)-3-hydroxyheptanoate (682 mg)

mp: 64-65° C.

NMR (CDCl₃, δ): 0.88 (3H, t, J=8 Hz), 1.20-1.52 (6H, m), 3.55 (1H, d,J=7 Hz), 3.82 (3H, s), 3.88 (3H, s), 4.10-4.21 (1H, m), 5.08 (1H, d,J=11 Hz), 5.18 (1H, d, J=11 Hz), 6.80-6.92 (3H, m), 7.20-7.35 (5H, m)

FAB MS m/z: 373 [M+H]⁺

Preparation 14-1)

To a solution of benzyl(2RS,3RS)-2-(1,4-benzodioxan-6-yl)-3-hydroxyheptanoate (720 mg) inmethanol (10 ml) was catalytically reduced with 10% palladium on carbon(100 mg) under 3 atmospheric pressure of hydrogen for 1 hour. Thecatalyst was removed by filtration and the filtrate was evaporated toafford (2RS,3RS)-2-(1,4-benzodioxan-6-yl)-3-hydroxyheptanoic acid (521mg).

NMR (CDCl₃, δ): 0.80-0.92 (3H, m), 1.08-1.55 (6H, m), 3.45-3.50 (1H, m),4.03-4.20 (1H, m), 4.24 (4H, s), 6.70-6.92 (3H, s)

FAB MS m/z: 281 [M+H]⁺

The following compounds were obtained in substantially the same manneras that of Preparation 14-1).

Preparation 14-2)

(2RS,3RS)-2-(2-Naphthyl)-3-hydroxyheptanoic acid (474 mg)

mp: 127-128° C.

NMR (CDCl₃, δ): 0.77 (3H, t, J=7 Hz), 1.10-1.52 (6H, m), 3.76 (1H, d,J=8 Hz), 4.24-4.53 (1H, m), 7.38-7.52 (3H, m), 7.75-7.85 (4H, m)

FAB MS m/z: 273 [M+H]⁺

Preparation 14-3)

(2RS,3RS)-2-(3,4-Dimethoxyphenyl)-3-hydroxyheptanoate (521 mg)

mp: 125-126° C.

NMR (CDCl₃, δ): 0.89 (3H, t, J=8 Hz), 1.25-1.57 (6H, m), 3.53 (1H, d,J=8 Hz), 3.87 (6H, s), 4.12-4.22 (1H, m), 6.80-6.96 (3H, m)

FAB MS m/z: 282 [M+H]⁺

The following compounds were obtained in substantially the same manneras that of Preparation 8-2).

Preparation 15-1)

Benzyl 3-hydroxy-2-(3,4-methylenedioxyphenyl)-4-phenylbutyrate (1.77 g)

NMR (CDCl₃, δ) 2.30-2.79 (4H, m), 3.55-3.62 (1H, m), 5.04-5.21 (2H, m),5.96, 5.97 (total 2H, s), 6.79 (2H, s), 6.88, 6.93 (total 1H, s),7.13-7.33 (10H, m)

Preparation 15-2)

Benzyl 3-hydroxy-2,3-bis(3,4-methylenedioxyphenyl)-propionate (1.87 g)

NMR (CDCl₃, δ): 3.77-3.82 (1H, m), 5.02-5.27 (3H, m), 5.88-5.99 (5H, m),6.50-7.08 (6H, m), 7.22-7.34 (5H, m)

Preparation 15-3)

Benzyl3-hydroxy-2-(3,4-methylenedioxyphenyl)-3-(3,4,5-trimethoxyphenyl)propionate(2.10 g)

NMR (CDCl₃, δ): 2.45 (0.3H, d, J=1 Hz), 3.02 (0.7H, d, J=3 Hz), 3.72,3.78 (total 9H, s), 4.90 (0.3H, d, J=14 Hz), 5.03-5.12 (1H, m), 5.08(0.3H, d, J=14 Hz), 5.13 (0.7H, d, J=14 Hz), 5.25 (0.7H, d, J=14 Hz),5.90 (1.4H, s), 5.98 (0.6H, s), 6.33 (1.4H, s), 6.52-6.66 (2H, m), 6.63(0.6H, s), 6.76-7.07 (1H, m), 7.24-7.35 (5H, m)

Preparation 15-4)

Benzyl3-hydroxy-2-(3,4-methylenedioxyphenyl)-3-(4-methoxycarbonylphenyl)propionate(2.02 g)

NMR (CDCl₃, δ): 3.76-3.94 (4H, m), 4.85-5.18 (3H, m), 5.89-6.00 (3H, m),6.57-7.04 (3H, m), 7.18-7.49 (7H, m), 7.72-7.93 (2H, m)

Preparation 15-5)

Benzyl 3-hydroxy-2-(3,4-methylenedioxyphenyl)-3-(4-biphenylyl)propionate(670 mg)

NMR (CDCl₃, δ): 3.06 (0.7H, d, J=4 Hz), 3.86-3.92 (1H, 10 m), 4.70(0.3H, d, J=6 Hz), 4.87 (0.3H, d, J=12 Hz), 5.04 (0.3H, d, J=12 Hz),5.12 (0.7H, d, J=12 Hz), 5.15-5.25 (1H, m), 5.24 (0.7H, d, J=12 Hz),5.88-5.99 (2H, m), 6.53-7.02 (3H, m), 7.18-7.60 (14H, m)

Preparation 15-6)

Benzyl3-hydroxy-2-(3,4-methylenedioxyphenyl)-3-(2-n-butyl-1-tert-butoxycarbonyl-1H-imidazol-4-yl)propionate(2.39 g)

NMR (CDCl₃, δ): 0.90-0.97 (3H, m), 1.31-1.42 (2H, m), 1.56, 1.57 (total9H, s), 1.58-1.71 (2H, m), 2.75 (0.5H, d, J=5 Hz), 2.89-2.98 (2H, m),3.38 (0.5H, d, J=7 Hz), 4.17 (0.5H, d, J=7 Hz), 4.23 (0.5H, d, J=9 Hz),4.96-5.05 (3H, m), 5.92, 5.95 (total 2H, s), 6.66-6.94 (3H, m),7.09-7.30 (6H, m)

Preparation 16-1)

(2RS,3RS)- and(2RS,3SR)-3-Hydroxy-2-(3,4-methylenedioxyphenyl)-4-phenylbutyric acidwas obtained in substantially the same manner as that of Preparation14-1).

The stereoisomers were separated by silica gel column chromatography(eluent; n-hexane:ethyl acetate=3:2) to give more polar isomer (136 mg)and less polar isomer (400 mg). The stereostructures of the more polarand the less polar isomers were assigned as (2RS,3RS)- and(2RS,3SR)-configurations respectively.

More polar isomer:

mp : 70-75° C.

NMR (DMSO-d₆, δ): 2.50-2.60 (2H, m), 3.12 (1H, d, J=7 Hz), 3.79-3.88(1H, m), 5.92 (2H, s), 6.69 (1H, d, J=8 Hz), 6.76 (1H, d, J=8 Hz), 6.88(1H, s), 7.10-7.18 (3H, m), 7.20-7.27 (2H, m)

Less polar isomer:

mp: 134-137° C.

NMR (DMSO-d₆, δ): 2.54 (1H, dd, J=9, 15 Hz), 2.70 (1H, dd, J=4, 15 Hz),3.40 (1H, d, J=8 Hz), 4.19 (1H, ddd, J=4, 8, 9 Hz), 5.98 (2H, s), 6.76(1H, d, J=8 Hz), 6.83 (1H, d, J=8 Hz), 6.92 (1H, s), 7.16-7.21 (3H, m),7.24-7.30 (2H, m)

Preparation 16-2)

(2RS,3SR)- and(2RS,3RS)-3-Hydroxy-2,3-bis(3,4-methylenedioxyphenyl)propionic acid wasobtained in substantially the same manner as that of Preparation 14-1).

The stereoisomers were separated by silica gel column chromatography(eluent; n-hexane:ethyl acetate=1:1) to give more polar isomer (309 mg)and less polar isomer (310 mg). The stereostructures of the more polarand the less polar isomers were assigned as (2RS,3SR)- and(2RS,3RS)-configurations respectively.

More polar isomer:

NMR (DMSO-d₆, δ): 3.62 (1H, d, J=10 Hz), 4.90 (1H, d, J=10 Hz),5.89-5.92 (4H, m), 6.57 (2H, dt, J=1, 6 Hz), 6.67 (2H, t, J=6 Hz), 6.80(2H, d, J=1 Hz)

FAB MS: 330 [M]⁺

Less polar isomer:

mp: 167-170° C.

NMR (DMSO-d₆, δ): 3.67 (1 H, d, J=9 Hz), 4.89 (1 H, d, J=9 Hz), 5.98(4H, s), 6.77-6.86 (4H, m), 6.90 (1H, s), 6.99 (1H, s)

Preparation 16-3)

(2RS,3SR)- and(2RS,3RS)-3-Hydroxy-2-(3,4-methylenedioxyphenyl)-3-(3,4,5-trimethoxyphenyl)propionicacid was obtained in substantially the same manner as that ofPreparation 14-1).

The stereoisomers were separated by silica gel column chromatography(eluent; n-hexane:ethyl acetate=2:3) to give more polar isomer (227 mg)and less polar isomer (190 mg). The stereostructures of the more polarand the less polar isomers were assigned as (2RS,3SR)- and(2RS,3RS)-configurations respectively.

More polar isomer:

mp: 139-142° C. NMR (DMSO-d₆, δ): 3.56 (3H, s), 3.62 (1H, d, J=10 Hz),3.64 (6H, s), 4.92 (1H, d, J=10 Hz), 5.92 (2H, s), 6.42 (2H, s), 6.59(1H, dd, J=1, 8 Hz), 6.69 (1H, d, J=8 Hz), 6.79 (1H, d, J=1 Hz)

FAB MS: 376 [M]⁺

Less polar isomer:

mp: 188-192° C.

NMR (DMSO-d₆, δ): 3.62 (3H, s), 3.70 (1H, d, J=9 Hz), 3.73 (6H, s), 4.96(1H, d, J=9 Hz), 5.98 (2H, s), 6.63 (2H, s), 6.75-6.84 (2H, m), 6.99(1H, s)

Preparation 16-4)

(2RS,3SR)- and(2RS,3RS)-3-Hydroxy-2-(3,4-methylenedioxyphenyl)-3-(4-methoxycarbonylphenyl)propionicacid was obtained in substantially the same manner as that ofPreparation 14-1).

The stereoisomers were separated by silica gel column chromatography(eluent; n-hexane:ethyl acetate=1:1) to give more polar isomer (260 mg)and less polar isomer (180 mg). The stereostructures of the more polarand the less polar isomers were assigned as (2RS,3SR)- and(2RS,3RS)-configurations respectively.

More polar isomer:

NMR (DMSO-d₆, δ): 3.60 (1H, d, J=9 Hz), 3.82 (3H, s), 5.03 (1H, d, J=9Hz), 5.90, 5.91 (total 2H, 5), 6.55 (1H, d, J=9 Hz), 6.66 (1H, d, J=9Hz), 6.80 (1H, s), 7.29 (2H, d, J=8 Hz), 7.75 (2H, d, J=8 Hz)

FAB MS: 327.1 [M−OH]⁺

Less polar isomer:

mp: 180-188° C.

NMR (DMSO-d₆, δ): 3.76 (1 H, d, J=8 Hz), 3.83 (3H, s), 5.10 (1 H, d, J=8Hz), 5.98 (2H, s), 6.75 (1 H, d, J=8 Hz), 6.79 (1H, d, J=8 Hz), 6.98(1H, s), 7.48 (2H, d, J=9 Hz), 7.88 (2H, d, J=9 Hz)

Preparation 16-5)

(2RS,3SR)- and (2RS,3RS)-3-Hydroxy-2-(3,4-methylenedioxyphenyl)-3-(4-biphenylyl)propionic acid was obtained in substantially the samemanner as that of Preparation 14-1).

The stereoisomers were separated by silica gel column chromatography(eluent; n-hexane:ethyl acetate=2:1-ethyl acetate-methanol) to give morepolar isomer (290 mg) and less polar isomer (155 mg). Thestereostructures of the more polar and the less polar isomers wereassigned as (2RS,3SR)- and (2RS,3RS)-configurations respectively.

More polar isomer:

NMR (DMSO-d₆, δ): 3.42 (1H, d, J=7 Hz), 4.78 (1H, d, J=7 Hz), 5.91, 5.93(total 2H, s), 6.69 (2H, s), 6.94 (1H, s), 7.29-7.36 (3H, m), 7.39-7.48(2H, m), 7.50 (2H, d, J=9 Hz), 7.61 (2H, d, J=9 Hz)

Less polar isomer:

NMR (DMSO-d₆, δ): 3.77 (1H, d, J=8 Hz), 5.03 (1H, d, J=8 Hz), 5.99 (2H,s), 6.84 (2H, s), 7.02 (1H, s), 7.32-7.37 (1H, m), 7.42-7.49 (4H, m),7.60 (2H, d, J=9 Hz), 7.67 (2H, d, J=9 Hz)

Preparation 16-6)

(2RS,3SR) and(2RS,3RS)-3-Hydroxy-2-(3,4-methylenedioxyphenyl)-3-(2-n-butyl-1-tert-butoxycarbonyl-1H-imidazol-4-yl)propionicacid was obtained in substantially the same manner as that ofPreparation 14-1).

The stereoisomers were separated by silica gel column chromatography(eluent; n-hexane:ethyl acetate=2:1) to give more polar isomer (824 mg)and less polar isomer (510 mg). The stereostructures of the more polarand the less polar isomers were assigned as (2RS,3SR)- and(2RS,3RS)-configurations respectively.

More polar isomer:

NMR (DMSO-d₆, δ): 0.89 (3H, t, J=8 Hz), 1.24-1.36 (2H, m), 1.50-1.63(2H, m), 1.56 (9H, s), 2.77-2.88 (2H, m), 3.60-3.64 (1H, br), 4.54-4.59(1H, br), 5.91 (2H, s), 6.64-7.10 (4H, m)

Less polar isomer:

NMR (DMSO-d₆, δ): 0.90 (3H, t, J=7 Hz), 1.23-1.39 (2H, m), 1.54-1.65(2H, m), 1.56 (9H, s), 2.88 (2H, t, J=8 Hz), 3.89 (1H, d, J=9 Hz), 4.90(1H, d, J=9 Hz), 5.98 (2H, s), 6.69-7.03 (4H, m)

Preparation 17

Benzyl (2RS,3SR)- and(2RS,3RS)-3-hydroxy-2-(3,4-methylenedioxyphenyl)-3-(2-pyridyl)propionatewas obtained in substantially the same manner as that of Preparation8-2).

The stereoisomers were separated by silica gel column chromatography(eluent; n-hexane:ethyl acetate=4:1˜2:1) to give more polar isomer (360mg) and less polar isomer (742 mg). The stereostructures of the morepolar and the less polar isomers were assigned as (2RS,3SR)- and(2RS,3RS)-configurations respectively.

More polar isomer:

NMR (CDCl₃, δ): 3.92 (1H, d, J=8 Hz), 4.41 (1H, d, J=8 Hz), 5.10-5.19(1H, m), 5.12 (1H, d, J=14 Hz), 5.25 (1H, d, J=14 Hz), 5.91 (2H, t, J=1Hz), 6.56-6.87 (4H, m), 7.12-7.22 (2H, m), 7.25-7.36 (4H, m), 7.44 (1H,dt, J=1, 8 Hz), 8.52 (1H, d, J=6 Hz)

Less polar isomer:

NMR (CDCl₃, δ): 3.85 (1H, d, J=7 Hz), 4.04 (1H, d, J=8 Hz), 5.00 (1H, d,J=13 Hz), 5.13 (1H, d, J=13 Hz), 5.36 (1H, dd, J=7, 8 Hz), 5.93 (2H, s),6.67 (2H, d, J=1 Hz), 6.86 (1H, s), 7.11-7.20 (4H, m), 7.26-7.32 (3H,m), 7.54 (1H, dt, J=1, 8 Hz), 8.50 (1H, dd, J=1, 6 Hz)

Preparation 18

(2RS,3SR)-3-Hydroxy-2-(3,4-methylenedioxyphenyl)-3-(2-pyridyl)propionicacid was obtained in substantially the same manner as that ofPreparation 14-1).

NMR (DMSO-d₆, δ): 3.90 (1H, d, J=10 Hz), 5.03 (1H, d, J=10 Hz), 5.90(2H, d, J=1 Hz), 6.57 (1H, d, J=8 Hz), 6.65 (1H, d, J=8 Hz), 6.77 (1H,s), 7.14 (1H, dd, J=6, 8 Hz), 7.30 (1H, d, J=8 Hz), 7.63 (1H, dt, J=1, 8Hz), 8.37 (1H, d, J=6 Hz)

FAB MS: 288.1 [M+H]⁺

Preparation 19

(2RS,3RS)-3-Hydroxy-2-(3,4-methylenedioxyphenyl)-3-(2-pyridyl)propionicacid was obtained in substantially the same manner as that ofPreparation 14-1).

NMR (DMSO-d₆, δ): 4.03 (1H, d, J=8 Hz), 5.14 (1H, d, J=8 Hz), 5.95 (2H,t, J=1 Hz), 6.62 (1 H, d, J=9 Hz), 6.72 (1H, d, J=9 Hz), 6.88 (1H, s),7.18-7.23 (1H, m), 7.27-7.31 (1H, m), 7.68 (1H, dt, J=1, 8 Hz), 8.48(1H, d, J=6 Hz)

FAB MS: 288.1 [M+H]⁺

Preparation 20

A solution of(2RS,3SR)-3-hydroxy-2-(3,4-methylenedioxy-phenyl)-3-(4-methoxycarbonylphenyl)propionicacid (80 mg) in 1N aqueous sodium hydroxide solution (1.2 ml) andmethanol (5 ml) was stirred at ambient temperature for 18 hours. Thereaction was quenched with iN-hydrochloric acid and then the resultingmixture was diluted with ethyl acetate. The layers were separated andthe organic layer was washed with brine. The organic layer was dried andevaporated to afford(2RS,3SR)-3-hydroxy-2-(3,4-methylenedioxyphenyl)-3-(4-carboxyphenyl)propionicacid (60 mg).

mp: >250° C.

NMR (DMSO-d₆, δ): 3.66 (1H, d, J=1 Hz), 5.07 (1H, d, J=11 Hz), 5.90,5.92 (total 2H, s), 6.55 (1H, d, J=10 Hz), 6.65 (1H, d, J=10 Hz), 6.78(1H, s), 7.26 (2H, d, J=9 Hz), 7.72 (2H, d, J=9 Hz)

Preparation 21

To a solution of 2-n-butyl-1H-imidazole-4-carbaldehyde (800 mg) andN,N-dimethylaminopyridine (65 mg) in acetonitrile (15 ml) was addeddi-tert-butyl dicarbonate (1.20 g) and the solution was stirred atambient temperature for 20 minutes. The mixture was evaporated in vacuoand then the residue was diluted with ethyl acetate. The organicsolution was washed successively with saturated aqueous ammoniumchloride solution, saturated aqueous sodium bicarbonate. The organiclayer was dried and evaporated to afford2-n-butyl-1-tert-butoxycarbonyl-1H-imidazole-4-carbaldehyde.

NMR (CDCl₃, δ): 0.97 (3H, t, J=8 Hz), 1.38-1.51 (2H, m), 1.65 (9H, s),1.70-1.82 (2H, m), 3.04 (2H, t, J=8 Hz), 7.99 (1H, s), 9.89 (1H, s)

Preparation 22

A solution of(2RS,3SR)-3-hydroxy-2-(3,4-methylenedioxyphenyl)-3-(2-n-butyl-1-tert-butoxycarbonyl-1H-imidazol-4-yl)propionicacid (250 mg) in 4N hydrogen chloride-ethyl acetate solution (3 ml) wasstirred at ambient temperature for 18 hours. The solution was evaporatedin vacuo and then the residue was solidified with ether. Resultingpowder was collected by filtration and dried to afford(2RS,3SR)-3-hydroxy-2-(3,4-methylenedioxyphenyl)-3-(2-n-butyl-1H-imidazol-4-yl)propionicacid hydrochloride (65 mg).

NMR (DMSO-d₆, δ): 0.80-0.90 (3H, m), 1.03-1.12 (2H, m), 1.53-1.66 (2H,m), 2.73-2.85 (2H, m),3.90 (1H, d, J=10 Hz), 5.12 (1H, d, J=10 Hz),5.92, 5.95 (total 2H, s), 6.62-6.84 (3H, m), 7.12 (1H, s)

FAB MS: 333.1 [M+H]⁺

Preparation 23-1)

Benzyloxycarbonyl-L-Trp(CH₂CO₂ ^(t)Bu)-OH was obtained according to asimilar manner to that of Preparation 29-1).

NMR (CDCl₃, δ): 1.39 (9H, s), 3.30-3.38 (2H, m), 4.62 (2H, s), 4.68-4.77(1H, m), 5.02-5.15 (2H, m), 5.31 (1H, d, J=7 Hz), 6.89 (1H, s),7.03-7.09 (1H, m), 7.15-7.19 (2H, m), 7.27-7.36 (4H, m), 7.55 (1H, d,J=7 Hz), 7.98 (1H, s)

ESI-MS (m/z): 453 [M+H]

Preparation 23-2)

Benzyloxycarbonyl-L-Trp(CH₂CO₂ ^(t)Bu)-OMe was obtained according to asimilar manner to that of Example 30-2).

NMR (CDCl₃, δ): 1.40 (9H, s), 3.25-3.30 (2H, m), 3.67 (3H, s), 4.62-4.73(3H, m), 5.00-5.15 (2H, m), 5.25-5.32 (1H, m), 6.80-6.87 (1H, m),7.05-7.11 (1H, m), 7.15-7.38 (7H, m), 7.50 (1H, d, J=7 Hz)

ESI-MS (m/z): 467 [M+H]

Preparation 23-3)

A solution of benzyloxycarbonyl-L-Trp(CH₂CO₂ ^(t)Bu)-OMe (1.00 g) intrifluoroacetic acid (200 ml) was stirred at ambient temperature for 30minutes. The solution was concentrated in vacuo and to the residue wasadded 0.5N hydrochloric acid (30 ml) and ethyl acetate (30 ml). Theorganic layer was washed with 0.5N hydrochloric acid (30 ml) and brine(30 ml) successively and the organic layer was dried over magnesiumsulfate. The solution was concentrated in vacuo to givebenzyloxycarbonyl-L-Trp(CH₂CO₂H)-OMe (1.57 g) as an oil.

Rf: 0.61 (silica gel, chloroform:methanol:acetic acid=16:1:1)

Preparation 23-4)

To a solution of benzyloxycarbonyl-L-Trp(CH₂CO₂H)-OMe (700 mg),dimethylamine monohydrochloride (167 mg) and 1-hydroxybenzotriazole (277mg) in N,N-dimethylformamide (5 ml) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (318 mg) under ice-bathcooling. After being stirred at ambient temperature overnight, themixture was poured into water (20 ml) and extracted with ethyl acetate(20 ml). The organic layer was washed with 0.5N hydrochloric acid (20ml×2), saturated aqueous sodium bicarbonate solution (20 ml×2) and brine(20 ml) successively and dried over magnesium sulfate. The solution wasconcentrated in vacuo and the residue was purified by preparative thinlayer silica gel chromatography (hexane:ethyl acetate, 1:3) to givebenzyloxycarbonyl-L-Trp(CH₂CONMe₂)-OMe (323 mg) as an oil.

NMR (CDCl₃, δ): 2.93 (6H, s), 3.20-3.32 (2H, m), 3.68 (3H, s), 4.65-4.74(1H, m), 4.82 (2H, s), 4.97-5.16 (2H, m), 5.28-5.37 (1H, m), 6.87 (1H,s), 7.02-7.10 (1H, m), 7.15-7.38 (7H, m), 7.50 (1H, d, J=7 Hz)

ESI-MS (m/z): 438 [M+H]

Preparation 23-5)

A mixture of benzyloxycarbonyl-L-Trp(CH₂CONMe₂)-OMe (305 mg) and 10%palladium on activated carbon (300 mg) in methanol (20 ml), water (2 ml)and hydrogen chloride (0.25 ml, 4N ethyl acetate solution) was shakenunder hydrogen atmosphere (3 atmospheric pressure) at ambienttemperature for 1 hour. The mixture was filtered through a bed of celiteand the filtrate was concentrated in vacuo. The residue was trituratedwith ethyl acetate to give HCl-H-L-Trp(CH₂CONMe₂)-OMe (211 mg) as anamorphous powder.

NMR (DMSO-d₆, δ): 2.84 (3H, s), 3.09 (3H, s), 3.18-3.35 (2H, m), 3.63(3H, s), 4.12-4.23 (1H, s), 5.08 (2H, s), 6.98-7.17 (3H, s), 7.34 (1H,d, J=7 Hz), 7.53 (1H, d, J=7 Hz), 8.64 (2H, s)

ESI-MS (m/z): 304 [M+H]

Preparation 24-1)

tert-Butoxycarbonyl-L-Trp(CH₂CH₂CO₂Et)-OMe was obtained as a slightlybrown oil according to a similar manner to that of Example 30-2).

NMR (CDCl₃, δ): 1.21 (3H, t, J=7 Hz), 1.45 (9H, s), 2.78 (2H, t, J=8Hz), 3.23-3.27 (2H, m), 3.70 (3H, s), 4.12 (2H, q, J=7 Hz), 4.40 (2H, t,J=8 Hz), 4.57-4.66 (1H, m), 5.00-5.07 (1H, m), 6.93 (1H, s), 7.10 (1H,t, J=8 Hz), 7.21 (1H, t, J=8 Hz), 7.28-7.37 (1H, m), 7.53 (1H, d, J=8Hz)

Preparation 24-2)

HCl.H-L-Trp(CH₂CH₂CO₂Et)-OMe was obtained as a slightly yellow solidaccording to a similar manner to that of Preparation 25-2).

NMR (DMSO-d₆, δ): 1.14 (3H, t, J=8 Hz), 2.80 (2H, t, J=7 Hz), 3.27 (2H,t, J=7 Hz), 3.67 (3H, s), 4.03 (2H, q, J=8 Hz), 4.21 (1H, t, J=7 Hz),4.38 (2H, t, J=7 Hz), 7.06 (1H, t, J=8 Hz), 7.17 (1H, t, J=8 Hz), 7.23(1H, s), 7.49 (1H, d, J=8 Hz), 7.52 (1H, d, J=8 Hz), 8.50-8.56 (2H, brs)

Preparation 25-1)

To a solution of Boc-L-Trp(CHO)-OH (1.00 g) and triethylamine (396 mg)in THF (tetrahydrofuran) (10 ml) was added pivaloyl chloride (399 mg) at−78° C. under nitrogen atmosphere. The mixture was stirred in ice bathfor 30 minutes. To the solution was added a mixture which wasmethanesulfone amide (430 mg) in DMSO (dimethyl sulfoxide) (10 ml) and1.0 M lithium bis(trimethylsilyl)amide in THF (9.1 ml) at roomtemperature. After being stirred for 5 hours at the same temperature,the reaction mixture was quenched by 1.0 M hydrochloric acid. Themixture was extracted with ethyl acetate (50 ml), and the solution waswashed with brine, dried over magnesium sulfate and concentrated invacuo. The residue was crystallized from diethyl ether and n-hexane togive Boc-L-Trp(CHO)-NHSO₂CH₃ (568 mg).

NMR (CDCl₃, δ): 1.30 (9H, s), 2.88-3.14 (3H, m), 3.22 (3H, s), 4.30-4.42(1H, m), 7.16-7.42 (3H, m), 7.56-7.74 (1H, m), 7.82-7.92 (1H, m),8.18-8.30 (1H, m)

ESI-MS: 410 [M+H]

Preparation 25-2)

The solution of Boc-L-Trp(CHO)-NHSO₂CH₃ (568 mg) in 4Nhydrogenchloride-ethyl acetate solution (20 ml) was stirred at roomtemperature for 30 minutes. After being evaporated in vacuo, the residuewas solidified with diethyl ether to give HCl.H-L-Trp(CHO)-NHSO₂CH₃ (420mg).

Preparation 26-1)

Benzyl3-hydroxy-3,3-di(2-pyridyl)-2-(3,4-methylenedioxyphenyl)propionate wasobtained as a slightly yellow amorphous powder according to a similarmanner to that of Preparation 15-6).

NMR (CDCl₃, δ): 4.86 (1H, d, J=13 Hz), 5.09 (1H, d, J=13 Hz), 5.38 (1H,s), 5.86 (2H, t, J=1 Hz), 6.24 (1H, s), 6.52 (1H, d, J=8 Hz), 6.60 (1H,d, J=8 Hz), 6.87 (1H, s), 7.01 (1H, dd, J=5, 7 Hz), 7.07-7.16 (3H, m),7.23-7.28 (3H, m), 7.48-7.60 (2H, m), 7.68 (1H, d, J=8 Hz), 7.76 (1H, d,J=8 Hz), 8.42 (2H, dd, J=1, 8 Hz)

ESI-MS: 454.9 [M+H]

Preparation 26-2)

3-Hydroxy-3,3-di(2-pyridyl)-2-(3,4-methylenedioxyphenyl)propionic acidwas obtained as a slightly amorphous powder according to a similarmanner to that of Preparation 16-6).

NMR (CDCl₃, δ): 5.23 (1H, s), 5.89 (2H, s), 6.57 (1H, d, J=8 Hz), 6.62(1H, d, J=8 Hz), 6.80 (1H, s), 7.09 (1H, dd, J=4, 7 Hz), 7.24 (1H, dd,J=4, 7 Hz), 7.53-7.64 (3H, m), 7.73 (1H, t, J=8 Hz), 8.38 (1H, d, J=4Hz), 8.52 (1H, d, J=4 Hz)

ESI-MS: 365 [M+H]

Preparation 27-1)

Ethyl 2-(3,4-methylenedioxyphenyl)-3-cyclopropyl-3-hydroxypropionate wasobtained according to a similar manner to that of Preparation 8-2).

NMR (CDCl₃, δ): −0.10-0.03 (1H, m), 0.20-0.58 (3H, m), 0.72-0.92 (1H,m), 1.18-1.29 (3H, m), 2.33-2.62 (1H, m), 3.36-3.57 (1H, m), 3.64 (1H,t, J=6 Hz), 4.07-4.23 (2H, m), 5.95 (2H, s), 6.73-6.96 (3H, m)

ESI-MS (m/z): 479 [M+H]

Preparation 27-2)

(2RS,3SR)-2-(3,4-Methylenedioxyphenyl)-3-cyclopropyl-3-hydroxypropionicacid was obtained according to a similar manner to that of Preparation8-3).

NMR (DMSO-d₆, δ): −0.05-0.03 (1H, m), 0.10-0.30 (3H, m), 0.68-0.92 (1H,m), 2.50 (1H, s), 3.13 (1H, t, J=6 Hz), 3.22 (1H, d, J=6 Hz), 5.93 (2H,s), 6.74 (2H, s), 6.91 (1H, s)

ESI-MS (m/z): 249 [M+H]

Preparation 28-1)

Benzyl(2RS,3SR)-3-hydroxy-3-(2-biphenylyl)-2-(3,4-methylenedioxyphenyl)propionatewas obtained as a colorless oil according to a similar manner to that ofPreparation 15-6).

NMR (CDCl₃, δ): 3.18 (1H, d, J=5 Hz), 3.87 (1H, d, J=9 Hz), 5.02 (1H, d,J=14 Hz), 5.13 (1H, d, J=14 Hz), 5.32 (1H, dd, J=5, 9 Hz), 5.96-5.99(2H, m), 6.16 (1H, d, J=8 Hz), 6.20 (1H, d, J=2 Hz), 6.48 (1H, d, J=8Hz), 6.93-6.98 (2H, br s), 7.08 (1H, d, J=9 Hz), 7.12-7.17 (2H, m),7.22-7.40 (12H, m), 7.65 (1H, d, J=9 Hz)

Preparation 28-2)

(2RS,3SR)-3-Hydroxy-3-(2-biphenylyl)-2-(3,4-methylenedioxyphenyl)propionicacid was obtained as a white amorphous powder according to a similarmanner to that of Preparation 16-6).

NMR (CDCl₃, δ): 3.69 (1H, d, J=11 Hz), 5.17 (1H, d, J=11 Hz), 5.90 (2H,d, J=5 Hz), 6.17 (1H, d, J=8 Hz), 6.18 (1H, s), 6.53 (1H, d, J=8 Hz),6.92 (1H, d, J=7 Hz), 6.98-7.05 (2H, br s), 7.18 (1H, t, J=7 Hz),7.29-7.46 (4H, m), 7.66 (1H, d, J=7 Hz)

ESI-MS: 363 [M+H]

Preparation 29-1)

To a solution of Boc-L-Trp-OBzl (5.00 g), tetra-n-butylammonium sulfate(43 mg) and NaOH (sodium hydroxide) (1.27 g) in methylene chloride (100ml) was added a solution of ethyl bromoacetate (5.29 g) in methylenechloride (50 ml) in an ice-bath cooling. After being stirred at roomtemperature for 2 days, the mixture was washed with 5% aqueous potassiumhydrogen sulfate solution, 1M aqueous sodium bicarbonate solution andbrine, dried over magnesium sulfate, and concentrated in vacuo to affordBoc-L-Trp(CH₂COOEt)-OBzl (6.10 g) as an oil.

NMR (CDCl₃, δ): 1.30 (3H, t, J=7 Hz), 1.42 (9H, s), 3.29 (2H, d, J=6Hz), 4.23 (2H, q, J=7 Hz), 4.09-4.26 (3H, m), 5.01-5.22 (2H, m),7.08-7.40 (9H, m), 7.54 (1H, d, J=9 Hz)

ESI-MS : 481 [M+H]

Preparation 29-2)

HCl.H-L-Trp(CH₂COOEt)-OBzl (4.50 g) was obtained according to a similarmanner to that of Preparation 25-2) as an amorphous powder.

NMR (DMSO-d₆, δ): 1.22 (3H, t, J=7 Hz), 3.19-3.30 (2H, m), 4.14 (2H, q,J=7 Hz), 4.23-4.31 (1H, m), 5.05 (2H, s), 5.10 (2H, dd, J=9, 18 Hz),7.08 (1H, t, J=8 Hz), 7.12-7.22 (4H, m), 7.29-7.36 (3H, m), 7.48 (1H, d,J=9 Hz), 7.58 (1H, d, J=9 Hz)

ESI-MS: 381 [M+H]

Preparation 30-1)

Boc-L-Trp(CH₂COOEt)-NHSO₂CH₃ (2.08 g) was obtained according to asimilar manner to that of Preparation 25-1) as an amorphous powder.

NMR (CDCl₃, δ): 1.25 (9H, s), 1.27 (3H, t, J=7 Hz), 3.10 (2H, s), 3.30(3H, s), 4.22 (2H, q, J=7 Hz), 4.40-4.52 (1H, m), 4.82 (2H, s),5.05-5.18 (1H, m), 6.95-7.04 (1H, m), 7.12-7.28 (3H, m), 7.60 (1H, d,J=7 Hz), 8.06-8.16 (1H, m)

ESI-MS: 468 [M+H]

Preparation 30-2)

HCl.H-L-Trp(CH₂COOEt)-NHSO₂CH₃ (1.00 g) was obtained according to asimilar manner to that of Preparation 25-2) as an amorphous powder.

ESI-MS: 368 [M+H]

Preparation 31-1)

To a solution of benzyl(2RS,3SR)-3-(1-tert-butoxycarbonyl-2-n-butylimidazol-4-yl)-3-hydroxy-2-(3,4-methylenedioxyphenyl)propionate(4.27 g) and triethylamine (909 mg) in dichloromethane (50 ml) was addeddropwise methanesulfonyl chloride (1.03 g) at ambient temperature andthe mixture was stirred for 2 hours. As the reaction was not completed,methanesulfonyl chloride (500 mg) and triethylamine (450 mg) were addedto the mixture and stirred at ambient temperature for additional 2hours. The solution was washed successively with saturated ammoniumchloride aqueous solution, saturated sodium bicarbonate aqueous solutionand brine. Drying, filtering and removal of the solvents afforded acrude intermediate methanesulfonate compound. A mixture of the abovemethanesulfonate compound and 1,8-diazabicyclo[5.4.0]undec-7-ene (3.47g) in tetrahydrofuran (60 ml) was stirred at ambient temperature for 30minutes. The resulting mixture was diluted with ethyl acetate followedby washing successively with saturated sodium bicarbonate aqueoussolution and brine. Drying, filtering and removal of the solventsafforded a crude product. The crude product was chromatographed onsilica gel (eluent; n-hexane:ethyl acetate=8:1-4:1) to give benzyl (EandZ)-3-(1-tert-butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propenoate(3.21 g) as a yellow oil.

NMR (CDCl₃, δ): 0.87-0.96 (3H, m), 1.26-1.44 (2H, m), 1.52, 1.59 (total9H, s), 1.56-1.75 (2H, m), 2.89-2.98 (2H, m), 5.23 (1H, s), 5.37 (1H,s), 5.96 (1H, s), 5.98 (1H, s), 6.39 (0.5H, s), 6.69 (0.5H, s),6.70-6.95 (3H, m), 7.29-7.38 (5H, m), 7.41 (0.5H, s), 7.79 (0.5H, s)

ESI-MS: 505 [M+H]

Preparation 31-2)

3-(1-tert-Butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionicacid was obtained as a white amorphous powder according to a similarmanner to that of Preparation 16-6).

NMR (CDCl₃, δ): 0.92 (3H, t, J=7 Hz), 1.32-1.41 (2H, m), 1.59 (9H, s),1.60-1.71 (2H, m), 2.88-2.97 (3H, m), 3.17-3.27 (1H, m), 3.95-4.01 (1H,br), 5.92 (2H, s), 6.72 (2H, s), 6.81 (1H, s), 6.98 (1H, s)

ESI-MS: 417 [M+H]

Preparation 32

1-tert-Butoxycarbonyl-2-n-propyl-4-(hydroxymethyl)-imidazole wasobtained as a slightly yellow oil according to a similar manner to thatof Preparation 33-1).

NMR (CDCl₃, δ): 1.00 (3H, t, J=8 Hz), 1.59 (9H, s), 1.69-1.81 (2H, m),2.68 (1H, t, J=6 Hz), 2.95 (2H, dd, J=8, 9 Hz), 4.55 (2H, d, J=6 Hz),7.24 (1H, s)

ESI-MS: 241 [M+H]

Preparation 33-1)

To a solution of 2-n-butyl-4-(hydroxymethyl)imidazole (2.95 g) andN,N-dimethylaminopyridine (234 mg) in acetonitrile (30 ml) was addeddi-tert-butyl dicarbonate (4.18 g) at 0° C. The solution was stirred atambient temperature for 40 minutes, and then the solvent was removed invacuo. The residue was diluted with ethyl acetate and the organicsolution was washed successively with saturated ammonium chlorideaqueous solution, saturated sodium bicarbonate aqueous solution andbrine. Drying, filtering and removal of the solvents afforded a crudeproduct. The crude product was chromatographed on silica gel (50 g,eluent; 10% methanol in chloroform) to give1-tert-butoxycarbonyl-2-n-butyl-4-(hydroxymethyl)imidazole (4.48 g) as acolorless oil.

NMR (CDCl₃, δ): 0.95 (3H, t, J=8 Hz), 1.36-1.46 (2H, m), 1.62 (9H, s),1.66-1.75 (2H, m), 2.59 (1H, dd, J=4, 7 Hz), 2.98 (2H, dd, J=7, 9 Hz),4.54 (2H, d, J=7 Hz), 7.23 (1H, s)

ESI-MS: 255 [M+H]

Preparation 33-2)

To a solution of1-tert-butoxycarbonyl-2-n-butyl-4-(hydroxymethyl)imidazole (4.43 g) indichloromethane (80 ml) was added triphenylphosphine (5.48 g) followedby carbon tetrabromide (6.93 g) at ambient temperature and the mixturewas stirred for 30 minutes. The solvent was removed in vacuo and theresidue was purified by silica gel column chromatography (eluent;n-hexane:ethyl acetate=4:1) to give1-tert-butoxycarbonyl-2-n-butyl-4-(bromomethyl)imidazole (5.09 g) as acolorless oil.

NMR (CDCl₃, δ): 0.96 (3H, t, J=7 Hz), 1.37-1.48 (2H, m), 1.60 (9H, s),1.67-1.76 (2H, m), 2.98 (2H, dd, J=7, 10 Hz), 4.40 (2H, s), 7.32 (1H,s).

ESI-MS: 317 [M+H]

Preparation 34-1)

To a solution of 3,4-methylenedioxyphenylacetic acid (20.0 g) andN,N-dimethylformamide (0.5 ml) in dichloromethane (250 ml) was addeddropwise oxalyl chloride (11.6 ml) at 0° C. and the reaction mixture wasstirred at ambient temperature for 20 minutes. Removal of the solventafforded a crude intermediate acid chloride compound. To a solution of(4S)-4-isopropyloxazolidin-2-one (13.7 g) in tetrahydrofuran (200 ml)was added dropwise n-butyl lithium (66.3 ml, 1.6M n-hexane solution) at−65˜−50° C. over 15 minutes and the solution was stirred at −65° C. for20 minutes. The mixture was added to a solution of the above acidchloride in dichloromethane (50 ml) at −65° C. and the mixture wasstirred for 1 hour. The temperature was raised to ambient temperatureand the reaction was quenched with saturated ammonium chloride aqueoussolution. The resulting solution was diluted with ethyl acetate and theorganic layer was washed successively with saturated sodium bicarbonateaqueous solution and brine. Drying, filtering and removal of thesolvents afforded a crude product (35 g). The crude product waschromatographed on silica gel (350 g, eluent; n-hexane-ethylacetate=4:1) to give(4S)-3-(3,4-methylenedioxyphenyl)acetyl-4-isopropyloxazolidin-2-one(23.36 g) as a white solid.

NMR (CDCl₃, δ): 0.80 (3H, d, J=7 Hz), 0.88 (3H, d, J=7 Hz), 2.30-2.40(1H, m), 4.09-4.29 (4H, m), 4.40-4.46 (1H, m), 5.94 (2H, s), 5.76 (1H,s), 5.78 (2H, d, J=14 Hz)

Preparation 34-2)

To a solution of(4S)-3-(3,4-methylenedioxyphenyl)-acetyl-4-isopropyloxazolidin-2-one(4.24 g) in tetrahydrofuran (80 ml) was added dropwise lithiumbis(trimethylsilyl)amide (26.2 ml, 1.0M tetrahydrofuran solution) at−60° C. and the solution was stirred at 0° C. for 1 hour. A solution of1-tert-butoxycarbonyl-2-n-butyl-4-(bromomethyl)imidazole (5.08 g) intetrahydrofuran (50 ml) was added to the above mixture at −50˜−40° C.,and then the resulting mixture was stirred at −25˜−20° C. for 4.5 hours.The reaction was quenched with saturated ammonium chloride aqueoussolution and the solution was extracted with ethyl acetate. The organiclayer was washed successively with saturated sodium bicarbonate aqueoussolution and brine. Drying, filtering and removal of the solventsafforded a crude product. The crude product was purified by columnchromatogaphy (eluent; n-hexane:ethyl acetate=4:1) to give(4S)-3-[3-(1-tert-butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-4-isopropyloxazolidin-2-one(4.88 g) as a yellow oil.

NMR (CDCl₃, δ): 0.72-0.90 (6H, m), 0.95 (3H, t, J=8 Hz), 1.35-1.43 (2H,m), 1.59, 1.61 (total 9H, s), 1.60-1.70 (2H, m), 2.27-2.37 (1H, m),2.80-2.95 (3H, m), 3.31-3.40 (1H, m), 4.10-4.40 (3H, m), 5.46 (1H, dd,J=6, 10 Hz), 5.92, 5.94 (total 2H, s), 6.71-6.96 (4H, m)

ESI-MS: 528 [M+H]

Preparation 34-3)

To a solution of benzyl alcohol (1.29 g) in tetrahydrofuran (60 ml) wasadded dropwise n-butyl lithium (6.6 ml, 1.6M n-hexane solution) at 2-8°C. and the mixture was stirred for 20 minutes. A solution of(4S)-3-[3-(1-tert-butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-4-isopropyloxazolidin-2-one(4.86 g) was added dropwise to the mixture and the resulting solutionwas stirred at 2° C. for 2 hours. The reaction was quenched withsaturated ammonium chloride aqueous solution, and then the solution wasextracted with ethyl acetate. The organic layer was washed successivelywith saturated sodium bicarbonate aqueous solution and brine. Drying,filtering and removal of the solvents afforded a crude product. Thecrude product was purified by a silica gel column chromatography(eluent; n-hexane:ethyl acetate=4:1) to give benzyl3-(1-tert-butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionate(2R:2S=1:4) (3.67 g) as a slightly yellow oil.

NMR (CDCl₃, δ): 0.94 (3H, t, J=8 Hz), 1.35-1.43 (2H, m), 1.58 (9H, s),1.62-1.71 (2H, m), 2.83-2.97 (3H, m), 3.20-3.30 (1H, m), 4.03-4.10 (1H,m), 5.00 (1H, d, J=14 Hz), 5.13 (1H, d, J=14 Hz), 5.94 (2H, s),6.70-6.91 (4H, m), 7.17-7.38 (5H, m)

ESI-MS: 507 [M+H]

Preparation 34-4)

The mixture of benzyl(2RS)-3-(1-tert-butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionate(2R:2S=1:4, 3.65 g) and 10% palladium on activated carbon (1.0 g) inmethanol (50 ml) and water (5 ml) was shaken under hydrogen atmosphere(3 atmospheric pressure) at ambient temperature for 1 hour. The catalystwas filtered through a bed of celite and the filtrate was evaporated invacuo. The residue was diluted with AcOEt (ethyl acetate) and theorganic layer was washed with brine. Drying, filtering and removal ofthe solvents afforded(2RS)-3-(1-tert-butoxycarbonyl)-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionicacid (2R:2S=1:4) (2.63 g) as a white solid.

NMR (CDCl₃, δ): 0.90 (3H, t, J=8 Hz), 1.25-1.38 (2H, m), 1.56-1.68 (2H,m), 1.59 (9H, s), 2.86-2.95 (3H, s), 3.19-3.28 (1H, m), 3.93-3.99 (1H,m), 5.92 (2H, s), 6.70 (2H, s), 6.79 (1H, s), 6.96 (1H, s)

ESI-MS: 417 [M+H]

Preparation 35-1)

tert-Butoxycarbonyl-L-Trp(CH₂CH₂CO₂Et)-OH was obtained as a slightlyyellow oil according to a similar manner to that of Preparation 29-1).

NMR (CDCl₃, δ): 1.20 (3H, t, J=7 Hz), 1.43 (9H, s), 2.88 (2H, t, J=7Hz), 3.25-3.35 (2H, m), 4.10 (2H, q, J=7 Hz), 4.39 (2H, t, J=7 Hz),4.58-4.66 (1H, br), 5.00-5.06 (1H, br), 7.00 (1H, s), 7.11 (1H, t, J=8Hz), 7.22 (1H, t, J=8 Hz), 7.31 (1H, d, J=8 Hz), 7.58 (1H, d, J=8 Hz)

Preparation 35-2)

tert-Butoxycarbonyl-L-Trp(CH₂CH₂CO₂Et)-OBzl was obtained as a colorlessoil according to a similar manner to that of Preparation 36-1).

NMR (CDCl₃, δ): 1.20 (3H, t, J=7 Hz), 1.44 (9H, s), 2.70 (2H, t, J=7Hz), 3.23-3.28 (2H, m), 4.07-4.15 (2H, m), 4.32 (2H, t, J=7 Hz),4.63-4.70 (1H, m), 5.02-5.13 (1H, m), 5.07 (1H, d, J=13 Hz), 5.13 (1H,d, J=13 Hz), 6.69 (1H, s), 7.09 (1H, t, J=8 Hz), 7.18-7.40 (7H, m), 7.52(1H, d, J=8 Hz)

Preparation 35-3)

HCl.H-L-Trp (CH₂CH₂CO₂Et) -OBzl hydrochloride was obtained as a slightlyyellow solid according to a similar manner to that of Preparation 25-2).

NMR (DMSO-d₆, δ): 1.12 (3H, t, J=8 Hz), 2.76 (2H, t, J=8 Hz), 3.20-3.34(2H, m), 4.02 (2H, q, J=8 Hz), 4.28 (1H, t, J=8 Hz), 4.34 (2H, t, J=8Hz), 5.05 (1H, d, J=13 Hz), 5.12 (1H, d, J=13 Hz), 7.05 (1H, t, J=8 Hz),7.13-7.20 (4H, m), 7.30-7.36 (3H, m), 7.49 (1H, d, J=8 Hz), 7.53 (1H, d,J=8 Hz), 8.56-8.62 (2H, br s)

Preparation 36-1)

To a suspension of tert-butoxycarbonyl-L-Trp(CH₂CO₂Et)-OH (900 mg) andpotassium carbonate (478 mg) in N,N-dimethylformamide (15 ml) was addedbenzyl bromide (395 mg) at ambient temperature and the mixture wasstirred for 2 hours, then the resulting mixture was filtered. Thefiltrate was diluted with ethyl acetate followed by washing successivelywith 0.5N hydrochloric acid, saturated sodium bicarbonate aqueoussolution and brine. Drying, filtering and removal of the solventsafforded tert-butoxycarbonyl-L-Trp(CH₂CO₂Et)-OBzl (1.15 g) as a brownoil.

NMR (CDCl₃, δ): 1.24 (3H, t, J=8 Hz), 1.42 (9H, s), 3.27-3.30 (2H, m),4.28 (2H, q, J=8 Hz), 4.65-4.73 (3H, m), 5.02-5.17 (3H, m), 7.08-7.13(1H, m), 7.18-7.35 (8H, m), 7.53 (1H, d, J=8 Hz)

Preparation 36-2)

To a solution of tert-butoxycarbonyl-L-Trp(CH₂CO₂Et)-OBzl (1.10 g) inethyl acetate (4 ml) was added 4N hydrogen chloride in ethyl acetate(2.3 ml) and the solution was stirred at ambient temperature for 3hours. The resulting suspension was diluted with n-hexane followed byfiltration to give HCl.H-L-Trp(CH₂CO₂Et)-OBzl (696 mg) as a slightlybrown solid.

NMR (DMSO-d₆, δ): 1.21 (3H, t, J=8 Hz), 3.20-3.40 (2H, m), 4.13 (2H, q,J=8 Hz), 4.23-4.32 (1H, br s), 5.03 (2H, s), 5.04 (1H, d, J=14 Hz), 5.13(1H, d, J=14 Hz), 7.07 (1H, t, J=8 Hz), 7.12-7.20 (4H, m), 7.29-7.36(3H, m), 7.39 (1H, d, J=8 Hz), 7.56 (1H, d, J=8 Hz), 8.56-8.64 (2H, brs)

Preparation 37-1)

tert-Butoxycarbonyl-L-Trp(Me)-OBzl was obtained as a colorless oilaccording to a similar manner to that of Preparation 36-1).

NMR (CDCl₃, δ): 1.42 (9H, s), 3.28 (2H, d, J=4 Hz), 3.65 (3H, s),4.65-4.72 (1H, m), 5.05 (1H, d, J=14 Hz), 5.14 (1H, d, J=14 Hz), 6.58(1H, s), 7.09 (1H, t, J=8 Hz), 7.18-7.35 (6H, m), 7.52 (1H, d, J=8 Hz),8.01 (1H, s)

Preparation 37-2)

HCl.H-L-Trp(Me)-OBzl was obtained as a white solid according to asimilar manner to that of Preparation 25-2).

NMR (DMSO-d₆, δ): 3.20-3.38 (2H, m), 3.69 (3H, s), 4.22-4.29 (1H, br),5.06 (1H, d, J=12 Hz), 5.10 (1H, d, J=12 Hz), 7.00-7.21 (5H, m),7.29-7.36 (3H, m), 7.40 (1H, d, J=8 Hz), 7.54 (1H, d, J=8 Hz), 8.57-8.64(2H, br s)

Preparation 38-1)

tert-Butoxycarbonyl-L-Trp(CH₂CO₂Bzl)-OBzl was obtained as a slightlyyellow oil according to a similar manner to that of Preparation 36-1).

NMR (CDCl₃, δ): 1.43 (9H, s), 3.26-3.29 (2H, br), 4.65-4.72 (3H, br s),4.99-5.16 (4H, m), 6.55 (1H, s), 7.08-7.38 (14H, m), 7.53 (1H, d, J=8Hz)

Preparation 38-2)

HCl.H-L-Trp(CH₂CO₂Bzl)-OBzl was obtained as a slightly yellow solidaccording to a similar manner to that of Preparation 25-2).

NMR (DMSO-d₆, δ) 3.20-3.32 (2H, m), 4.26-4.33 (1H, m), 5.02 (1H, d, J=13Hz), 5.09-5.18 (5H, m), 7.07 (1H, t, J=8 Hz), 7.13-7.20 (4H, m),7.29-7.34 (9H, m), 7.56 (1H, d, J=8 Hz), 8.52-8.60 (2H, br s)

ESI-MS: 443 [M+H]

Preparation 39-1)

tert-Butoxycarbonyl-L-Trp(Et)-OBzl was obtained as a slightly yellow oilaccording to a similar manner to that of Preparation 35-1) by usingethyl iodide and to that of Preparation 36-1).

NMR (CDCl₃, δ): 1.37 (3H, t, J=8 Hz), 1.40 (9H, s), 3.28 (2H, d, J=6Hz), 4.02 (2H, q, J=8 Hz), 4.65-4.72 (1H, m), 5.06 (1H, d, J=11 Hz),5.14 (1H, d, J=11 Hz), 7.08 (1H, t, J=8 Hz), 7.16-7.36 (9H, m), 7.53(1H, d, J=8 Hz)

Preparation 39-2)

HCl.H-L-Trp(Et)-OBzl was obtained as a white solid according to asimilar manner to that of Preparation 25-2).

NMR (DMSO-d₆, δ): 1.30 (3H, t, J=8 Hz), 3.20-3.36 (2H, m), 4.10 (2H, q,J=8 Hz), 4.28 (1H, t, J=7 Hz), 5.07 (1H, d, J=11 Hz), 5.13 (1H, d, J=11Hz), 7.04 (1H, t, J=8 Hz), 7.12-7.20 (4H, m), 7.30-7.35 (3H, m), 7.47(1H, d, J=9 Hz), 7.54 (1H, d, J=9 Hz), 8.52-8.58 (2H, br s)

Preparation 40-1)

Ethyl3-(1-tert-butoxycarbonylimidazol-4-yl)-3-hydroxy-2-(3,4-methylenedioxyphenyl)propionatewas obtained as a yellow amorphous powder according to a similar mannerto that of Preparation 8-2).

NMR (CDCl₃, δ): 1.14-1.28 (3H, m), 1.59, 1.60 (total 9H, s), 2.94 (0.5H,d, J=4 Hz), 3.55 (0.5H, d, J=8 Hz), 4.04-4.21 (3H, m), 5.06 (0.5H, t,J=8 Hz), 5.26 (0.5H, dd, J=4, 8 Hz), 5.92 (0.5H, s), 5.95 (0.5H, s),6.68-6.78 (2H, m), 6.84 (0.5H, d, J=2 Hz), 6.88 (0.5H, s), 7.07 (0.5H,s), 7.21 (0.5H, s), 7.97 (0.5H, s), 8.03 (0.5H, s)

ESI-MS 405 [M+H]

Preparation 40-2)

Ethyl (E andZ)-3-(1-tert-butoxycarbonylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)-2-propenoatewas obtained as a white solid according to a similar manner to that ofPreparation 31-1).

Less Polar Diastereomer

NMR (CDCl₃, δ): 1.36 (3H, t, J=7 Hz), 1.62 (9H, s), 4.40 (2H, q, J=7Hz), 5.98 (2H, s), 6.72 (1H, s), 6.80 (1H, d, J=8 Hz), 6.94 (1H, d, J=8Hz), 6.98 (1H, s), 7.48 (1H, s), 8.03 (1H, s)

ESI-MS: 387 [M+H]

More Polar Diastereomer

NMR (CDCl₃, δ): 1.30 (3H, t, J=8 Hz), 1.56 (9H, s), 4.24 (2H, q, J=8Hz), 6.00 (2H, s), 6.52 (1H, s), 6.69-6.73 (2H, m), 6.89 (1H, d, J=8Hz), 7.79 (1H, s), 7.98 (1H, s)

ESI-MS: 387 [M+H]

Preparation 40-3)

Ethyl3-(1-tert-butoxycarbonylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionatewas obtained as a yellow oil according to a similar manner to that ofPreparation 16-6).

NMR (CDCl₃, δ): 1.18 (3H, t, J=8 Hz), 1.59 (9H, s), 2.90 (1H, dd, J=7,15 Hz), 3.28 (1H, dd, J=9, 15 Hz), 3.88 (1H, dd, J=7, 9 Hz), 4.02-4.17(2H, m), 5.94 (2H, s), 6.73 (1H, d, J=8 Hz), 6.78 (1H, d, J=8 Hz), 6.86(1H, s), 7.01 (1H, s), 7.97 (1H, s)

ESI-MS: 389 [M+H]

Preparation 40-4)

A solution of ethyl3-(1-tert-butoxycarbonylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionate(633 mg) in trifluoroacetic acid (5 ml) was stirred at ambienttemperature for 10 minutes. Trifluoroacetic acid was removed byevaporation and the residue was diluted with ethyl acetate followed bywashing successively with saturated sodium bicarbonate aqueous solutionand brine. Drying, filtering and removal of the solvents afforded acrude intermediate compound. To a solution of the above compound andtriethylamine (214 mg) in dichloromethane (10 ml) was added portionwisetriphenylmethyl chloride (545 mg) and the mixture was stirred at ambienttemperature for 20 minutes. The resulting solution was washedsuccessively with saturated ammonium chloride aqueous solution andsaturated sodium bicarbonate aqueous solution. Drying, filtering andremoval of the solvents afforded ethyl3-[1-(triphenylmethyl)imidazol-4-yl]-2-(3,4-methylenedioxyphenyl)propionate(740 mg) as a slightly yellow oil.

NMR (CDCl₃, δ): 1.15 (3H, t, J=8 Hz), 2.90 (1H, dd, J=8, 14 Hz), 3.25(1H, dd, J=7, 14 Hz), 3.92 (1H, dd, J=7, 8 Hz), 3.99-4.14 (2H, m), 5.92(2H, s), 6.33 (1H, s), 6.70 (2H, s), 6.81 (1H, s), 7.00-7.05 (6H, m),7.25-7.32 (10H, m)

Preparation 40-5)

The mixture of ethyl3-[1-(triphenylmethyl)imidazol-4-yl]-2-(3,4-methylenedioxyphenyl)propionate(730 mg) in 1N sodium hydroxide aqueous solution (4.1 ml) and ethanol(10 ml) was stirred at ambient temperature for 3 hours. The resultingsolution was neutralized with 1N hydrochloric acid (4 ml) followed bydilution with ethyl acetate, and then the organic layer was washed withbrine. Drying, filtering and removal of the solvents afforded3-[1-(triphenylmethyl)-imidazol-4-yl]-2-(3,4-methylenedioxyphenyl)propionicacid (650 mg) as a white solid.

Rf: 0.19 (10% methanol in chloroform)

Preparation 41-1)

Methyl3-[1-(triphenylmethyl)imidazol-4-yl]-2-(3,4-methylenedioxyphenyl)propionatewas obtained as a white powder according to a similar manner to that ofExample 30-2).

NMR (CDCl₃, δ): 2.93 (1H, dd, J=7, 15 Hz), 3.25 (1H, dd, J=8, 15 Hz),3.59 (3H, s), 3.96 (1H, dd, J=7, 8 Hz), 5.93 (2H, s), 6.34 (1H, s), 6.70(2H, s), 6.80 (1H, s), 7.00-7.06 (5H, m), 7.26-7.36 (11H, m)

ESI-MS: 517 [M+H]

Preparation 41-2)

To a solution of methyl3-[1-(triphenylmethyl)imidazol-4-yl]-2-(3,4-methylenedioxyphenyl)propionate(430 mg) in acetonitrile (30 ml) was added methyl iodide (708 mg) andthe mixture was stirred at ambient temperature for 60 hours. Removal ofthe solvents gave an iodonium salt. A mixture of the above iodonium saltin 80% acetic acid-water (10 ml) was stirred at 60° C. for 1.5 hours.The resulting mixture was cooled to ambient temperature and the solutionwas diluted with water. Carbinol was removed by filtration and thefiltrate was neutralized with saturated sodium bicarbonate aqueoussolution. The aqueous layer was extracted with ethyl acetate and theorganic layer was washed with saturated sodium bicarbonate aqueoussolution. Drying, filtering and removal of the solvents afforded a crudeproduct. The crude product was chromatographed on silica gel (eluent; 3%methanol in chloroform) to give methyl3-(1-methylimidazol-5-yl)-2-(3,4-methylenedioxyphenyl)propionate (176mg) as a colorless oil.

NMR (CDCl₃, δ): 2.90 (1H, dd, J=7, 15 Hz), 3.29 (1H, dd, J=9, 15 Hz),3.48 (3H, s), 3.65 (1H, s), 3.79 (1H, dd, J=7, 9 Hz), 5.96 (2H, s),6.73-6.77 (3H, m), 6.82 (1H, s), 7.33 (1H, s)

ESI-MS: 289 [M+H]

Preparation 41-3)

3-(1-Methylimidazol-5-yl)-2-(3,4-methylenedioxyphenyl)propionic acid wasobtained as a slightly yellow powder according to a similar manner tothat of Preparation 40-5).

NMR (DMSO-d₆, δ): 2.75 (1H, dd, J=7, 15 Hz), 3.13 (1H, dd, J=8, 15 Hz),3.48 (3H, s), 3.64 (1H, dd, J=7, 8 Hz), 5.96 (2H, s), 6.52 (1H, s), 6.76(1H, d, J=8 Hz), 6.79 (1H, d, J=8 Hz), 6.92 (1H, s), 7.39 (1H, s)

ESI-MS: 275 [M+H]

Preparation 42-1)

1-t-Butoxycarbonyl-2-ethyl-4-(hydroxymethyl)imidazole was obtainedaccording to a similar manner to that of Preparation 33-1).

NMR (CDCl₃, δ): 1.30 (3H, t, J=7 Hz), 1.10 (9H, s), 3.00 (2H, q, J=8Hz), 3.08-3.22 (1H, m), 4.54 (2H, s), 7.24 (1H, s)

ESI-MS (m/z): 227 [M+H]

Preparation 42-2)

1-t-Butoxycarbonyl-2-ethyl-4-(bromomethyl)imidazole was obtainedaccording to a similar manner to that of Preparation 33-2).

NMR (CDCl₃, δ) 1.31 (3H, t, J=7 Hz), 1.60 (9H, s), 3.00 (2H, q, J=6 Hz),4.39 (2H, s), 7.33 (1H, s)

Preparation 42-3)

(4S)-3-[3-(1-t-Butoxycarbonyl-2-ethylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-4-isopropyloxazolidinonewas obtained according to a similar manner to that of Preparation 34-2).

NMR (CDCl₃, δ): 0.72 (3H, d, J=7 Hz), 0.85 (3H, d, J=7 Hz), 1.24-1.29(3H, m), 1.58 (4.5H, s), 1.65 (4.5H, s), 2.25-2.37 (1H, m), 2.81-2.98(3H, m), 3.33-3.41 (1H, m), 4.08-4.15 (2H, m), 4.33-4.38 (1H, m),5.43-5.50 (1H, m), 5.91 (2H, s), 6.73 (1H, d, J=7 Hz), 6.88-6.97 (3H, m)

ESI-MS (m/z): 500 [M+H]

Preparation 42-4)

Benzyl3-(1-t-butoxycarbonyl-2-ethylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionatewas obtained according to a similar manner to that of Preparation 34-3).

NMR (CDCl₃, δ): 1.27 (3H, t, J=7 Hz), 1.57 (4.5H, s), 1.63 (4.5H, s),2.82-2.98 (3H, m), 3.21-3.30 (1H, m), 4.02-4.15 (1H, m), 4.98-5.16 (2H,m), 5.92 (2H, s), 6.70-6.90 (4H, m), 7.15-7.27 (4H, m), 7.37 (1H, d, J=6Hz)

ESI-MS (m/z): 479 [M+H]

Preparation 42-5)

3-(1-t-Butoxycarbonyl-2-ethylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionicacid was obtained according to a similar manner to that of Preparation16-6).

NMR (CDCl₃, δ): 1.21 (3H, t, J=7 Hz), 1.68 (9H, s), 2.82-2.97 (3H, m),3.18-3.28 (1H, m), 3.90-3.98 (1H, m), 5.90 (2H, s), 6.69 (2H, s), 6.79(1H, s), 6.96 (1H, s)

ESI-MS (m/z): 389 [M+H]

Preparation 43-1)

1-tert-Butoxycarbonyl-2-n-propyl-4-bromomethylimidazole was obtained asa slightly yellow oil according to a similar manner to that ofPreparation 33-2).

NMR (CDCl₃, δ): 1.00 (3H, t, J=8 Hz), 1.60, 1.63 (total 9H, s),1.67-1.81 (2H, m), 2.96 (2H, dd, J=8, 9 Hz), 4.39 (2H, s), 7.33 (1H, s)

Preparation 43-2)

(4S)-3-[3-(1-tert-Butoxycarbonyl-2-n-propylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-4-isopropyloxazolidin-2-onewas obtained as a yellow oil according to a similar manner to that ofPreparation 34-2).

NMR (CDCl₃, δ): 0.70-1.00 (6H, m), 0.98 (3H, t, J=8 Hz), 1.58, 1.61(total 9H, s), 1.66-1.77 (2H, m), 2.26-2.36 (1H, m), 2.82-2.93 (3H, m),3.32-3.40 (1H, m), 4.08-4.40 (4H, m), 5.47 (1H, dd, J=4, 9 Hz), 5.92,5.95 (total 2H, s), 6.74 (1H, t, J=8 Hz), 6.87-6.96 (2H, m)

ESI-MS: 514 [M+H]

Preparation 43-3)

Benzyl(2RS)-3-(1-tert-butoxycarbonyl-2-n-propylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionate(2R:2S=1:4) was obtained as a slightly yellow oil according to a similarmanner to that of Preparation 34-3).

NMR (CDCl₃, δ): 0.98 (3H, t, J=8 Hz), 1.58, 1.62 (total 9H, s),1.66-1.74 (2H, m), 2.85-2.94 (2H, m), 3.20-3.29 (1H, m), 4.04-4.10 (1H,m), 5.01 (1H, d, J=12 Hz), 5.14 (1H, d, J=12 Hz), 5.94 (2H, s),6.70-6.81 (2H, m), 6.84-6.91 (1H, m), 7.16-7.20 (1H, m), 7.25-7.39 (6H,m)

ESI-MS: 493 [M+H]

Preparation 43-4)

(2RS)-3-(1-tert-Butoxycarbonyl-2-n-propylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionicacid (2R:2S=1:4) was obtained as a white solid according to a similarmanner to that of Preparation 16-6).

mp: 129-132° C.

NMR (CDCl₃, δ): 0.94 (3H, t, J=9 Hz), 1.57 (9H, s), 1.62-1.73 (2H, m),2.85-2.95 (3H, br), 3.18-3.29 (1H, m), 3.89-3.97 (1H, br), 5.88-5.92(2H, br s), 6.68-6.73 (2H, br s), 6.80 (1H, s), 6.94-6.98 (1H, br s)

ESI-MS: 403 [M+H]

Preparation 44-1)

1-t-Butoxycarbonyl-2-pentyl-4-(hydroxymethyl)imidazole was obtainedaccording to a similar manner to that of Preparation 33-1).

NMR (CDCl_(31 δ):) 0.89 (3H, t, J=7 Hz), 1.27-1.42 (4H, m), 1.60 (9H,s), 1.65-1.78 (2H, m), 2.42 (1H, t, J=6 Hz), 2.98 (2H, t, J=7 Hz), 4.53(2H, d, J=6 Hz), 7.24 (1H, d, J=6 Hz)

ESI-MS (m/z): 269 [M+H]

Preparation 44-2)

1-t-Butoxycarbonyl-2-pentyl-4-(bromomethyl)imidazole was obtainedaccording to a similar manner to that of Preparation 33-2).

Rf: 0.53 (hexane:ethyl acetate=4:1)

Preparation 44-3)

(4S)-3-[3-(1-t-Butoxycarbonyl-2-pentylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-4-isopropyloxazolidin-2-onewas obtained according to a similar manner to that of Preparation 34-2).

NMR (CDCl₃, δ): 0.72-0.93 (9H, m), 1.30-1.40 (4H, m), 1.55-1.61 (9H, m),1.62-1.80 (2H, m), 2.25-2.38 (1H, m), 2.81-2.95 (3H, m), 3.32-3.40 (1H,m), 4.08-4.38 (3H, m), 5.42-5.48 (1H, m), 5.91-5.93 (2H, m), 6.70-6.97(4H, m)

ESI-MS (m/z): 542 [M+H]

Preparation 44-4)

Benzyl3-(1-t-butoxycarbonyl-2-pentylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionatewas obtained according to a similar manner to that of Preparation 34-3).

NMR (CDCl₃, δ): 0.86-0.91 (3H, m), 1.27-1.36 (4H, m), 1.57 (9H, s),1.57-1.75 (2H, m), 2.82-2.92 (3H, m), 3.19-3.28 (1H, m), 4.02-4.12 (1H,m), 4.97-5.15 (2H, m), 5.93 (2H, s), 6.70-6.90 (4H, m), 7.15-7.35 (5H,m)

ESI-MS (m/z): 521 [M+H]

Preparation 44-5)

3-(1-t-Butoxycarbonyl-2-pentylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionicacid was obtained according to a similar manner to that of Preparation16-6).

NMR (CDCl₃, δ): 0.87-0.92 (3H, m), 1.28-1.35 (4H, m), 1.57 (9H, s),1.60-1.73 (2H, m), 2.89-2.95 (3H, m), 3.18-3.27 (1H, m), 3.95-4.00 (1H,m), 5.91 (2H, s), 6.70 (2H, s), 6.78 (1H, s), 6.95 (1H, s)

ESI-MS (m/z): 431 [M+H]

Example 1-1)

To a solution of(2RS,3RS)-2-(2-benzyloxyphenylmethyl)-3-cyclohexyl-3-hydroxypropionicacid (111 mg) in dimethylformamide (3 ml) were added L-tryptophan benzylester hydrochloride (198 mg), 1-hydroxybenzotriazole hydrate (60.8 mg),1,3-dicyclohexylcarbodiimide (80.5 mg) and 4-methylmorpholine (91 mg)successively. After being stirred for 16 hours at ambient temperature,the mixture was poured into a mixture of diethyl ether and aqueous 1Nhydrochloric acid solution. The organic layer was separated and theaqueous layer was extracted with diethyl ether. The combined organiclayer was washed with aqueous bicarbonate solution and brine, dried andevaporated under reduced pressure. The residue was purified bychromatography to affordN-[(2RS,3RS)-2-(2-benzyloxyphenylmethyl)-3-cyclohexyl-3hydroxypropionyl]-L-tryptophan benzyl ester (171 mg).

NMR (CDCl₃, δ): 0.60-2.00 (12H, m), 2.68-3.47 (6H, m), 4.81-5.06 (5H,m), 6.12-7.83 (21H, m)

The following compounds were obtained in substantially the same manneras that of Example 1-1).

Example 1-2)

N-[(2RS,3SR)-2-(2-Benzyloxyphenylmethyl)-3-cyclohexyl-3-hydroxypropionyl]-L-tryptophanBenzyl Ester

NMR (CDCl₃, δ): 0.57-2.03 (12H, m), 2.63-3.46 (6H, m), 4.61-5.06 (5H,m), 5.82-7.91 (21H, m)

Example 2-1)

N-[(2RS,3SR)-2-(2-Benzyloxyphenyl)-3-cyclohexyl-3-hydroxypropionyl]-L-tryptophanBenzyl Ester

NMR (CDCl₃, δ): 0.85-1.80 (10H, m), 1.95-2.10 (1H, m), 3.12-3.20 (2H,m), 3.96-4.25 (3H, m), 4.69-5.04 (5H, m), 6.02 (0.5H, d, J=2.4 Hz), 6.43(1H, d, J=7.4 Hz), 6.52 (0.5H, d, J=2.4 Hz), 6.80-7.41 (18H, m), 7.56(0.5H, s), 7.67 (0.5H, s), 7.83-7.94 (1H, m)

Example 2-2)

N-[(2RS,3RS)-2-(2-Benzyloxyphenyl)-3-cyclohexyl-3-hydroxypropionyl]-L-tryptophanBenzyl Ester

NMR (CDCl₃, δ): 0.80-1.75 (11H, m), 3.13-3.22 (2H, m), 3.96-4.11 (3H,m), 4.78-5.04 (5H, m), 6.16 (0.5H, d, J=2.4 Hz), 6.30 (0.5H, d, J=6.1Hz), 6.33 (0.5H, d, J=7.3 Hz), 6.63 (0.5H, d, J=2.4 Hz), 6.79-7.48 (18H,m), 7.65 (0.5H, s), 7.75 (0.5H, s)

Example 3-1)

N-[(2RS,3SR)-4-(2-Benzyloxyphenyl)-2-{1-cyclohexyl-1-(hydroxy)methyl}butyryl]-L-tryptophanBenzyl Ester

NMR (CDCl₃, δ): 0.80-1.80 (11H, m), 1.80-2.10 (2H, m), 2.10-2.25 (1H,m), 2.51-2.63 (2H, m), 3.23-3.55 (4H, m), 4.93-5.18 (5H, m), 6.32 (0.5H,d, J=8.2 Hz), 6.40 (0.5H, d, J=8.0 Hz), 6.73-7.54 (18H, m), 7.81 (0.5H,s), 7.93 (0.5H, s)

Example 3-2)

N-[(2RS,3RS)-4-(2-Benzyloxyphenyl)-2-{1-cyclohexyl-1-(hydroxy)methyl}butyryl]-L-tryptophanBenzyl Ester

NMR (CDCl₃, δ): 0.80-2.10 (13H, m), 2.20-2.35 (1H, m), 2.54-2.80 (2H,m), 3.01-3.08 (1H, m), 3.21-3.31 (3H, m), 4.93-5.10 (5H, m), 6.26 (0.5H,d, J=8.0 Hz), 6.40 (0.5H, d, J=8.2 Hz), 6.80-7.54 (18H, m), 7.83 (0.5H,s), 7.92 (0.5H, s)

Example 4

N-[(2RS,3SR)-3-Cyclohexyl-3-hydroxy-2-(2-methoxyphenylmethyl)propionyl]-L-tryptophanBenzyl Ester

NMR (CDCl₃, δ): 0.70-1.80 (10H, m), 2.05-2.11 (1H, m), 2.67-3.26 (4H,m), 3.52-3.60 (1H, m), 3.61 (1.5H, s), 3.76 (1.5H, s), 3.98 (0.5H, d,J=1.7 Hz), 4.14 (0.5H, d, J=2 Hz), 4.62-4.90 (1H, m), 4.97-5.01 (3H, m),5.97 (0.5H, d, J=8.0 Hz), 6.09 (0.5H, d, J=8.0 Hz), 6.26-7.57 (14H, m),7.90 (0.5H, s), 7.99 (0.5H, s)

Example 5

N-[2-(2-Benzyloxycarbonylphenylmethyl)-3-cyclohexyl-3-hydroxypropionyl]-L-tryptophanBenzyl Ester

NMR (CDCl₃, δ): 0.80-1.80 (11H, m), 1.85-2.05 (1H, m), 2.71-2.81 (1H,m), 2.96-3.52 (5H, m), 3.80 (0.5H, d, J=3.1 Hz), 4.00 (0.5H, d, J=3.0Hz), 4.68-4.74 (1H, m), 4.98 (2H, s), 5.19 (1H, s), 5.31 (1H, dd, J=12.3and 18.6 Hz), 6.02 (0.5H, d, J=7.9 Hz), 6.32 (0.5H, d, J=2.4 Hz), 6.49(0.5H, d, J=7.6 Hz), 6.66 (0.5H, d, J=2.3 Hz), 7.02-7.46 (16H, m), 7.70(0.5H, s), 7.75 (0.5H, d, J=7.5 Hz), 7.84 (0.5H, d, J=7.5 Hz), 7.89(0.5H, s)

Example 6-1)

N-[(2S,3S)-2-(2-Benzyloxyphenyl)-3-cyclohexyl-3-hydroxypropionyl]-L-tryptophanBenzyl Ester

NMR (CDCl₃, δ): 0.80-1.75 (11H, m), 3.12-3.16 (2H, m), 3.95-4.15 (3H,m), 4.79 (2H, s), 4.85-4.98 (1H, m), 5.04 (2H, s), 6.18 (1H, d, J=2.4Hz), 6.29 (1H, d, J=7.6 Hz), 6.81-7.37 (20H, m), 7.65 (1H, s)

[a]_(D) ²⁴: −35.4° (C=0.56, CH₂Cl₂)

Example 6-2)

N-[(2R,3R)-2-(2-Benzyloxyphenyl)-3-cyclohexyl-3-hydroxypropionyl]-L-tryptophanBenzyl Ester

NMR (CDCl₃, δ): 0.80-1.40 (5H, m), 1.40-1.75 (6H, m), 3.20 (2H, d, J=5.7Hz), 4.08-4.14 (3H, m), 4.79-5.04 (5H, m), 6.32 (1H, d, J=7.9 Hz), 6.63(1H, d, J=2.4 Hz), 6.79-7.48 (20H, m), 7.74 (1H, s)

[a]_(D) ²⁴ 27.8° (C=0.56, CH₂Cl₂)

Example 6-3)

N-[(2R,3R)-2-(2-Benzyloxyphenyl)-3-cyclohexyl-3-hydroxypropionyl]-1-methyl-L-tryptophanBenzyl Ester

NMR (CDCl₃, δ): 0.9-1.80 (11H, m), 3.19 (2H, d, J=5.6 Hz), 3.55 (1H, s),4.05 (2H, s), 4.20 (1H, s), 4.71-5.02 (6H, m), 6.30 (1H, d, J=8.0 Hz),6.44 (1H, s), 6.78-7.46 (17H, m)

[α]_(D) ³⁰: 17.4° (C=0.88, CH₂Cl₂)

Example 7-1)

To a solution ofN-[(2RS,3RS)-2-(2-benzyloxyphenylmethyl)-3-cyclohexyl-3-hydroxypropionyl]-L-tryptophanbenzyl ester (150 mg) in methanol (3 ml) was added 10% palladium oncarbon (45 mg) and the mixture was stirred under hydrogen atmosphere for3 hours. The mixture was filtered and the filtrate was evaporated underreduced pressure to giveN-[(2RS,3RS)-3-cyclohexyl-3-hydroxy-2-(2-hydroxyphenylmethyl)propionyl]-L-tryptophan(128 mg).

NMR (CD₃OD, δ): 0.77-1.80 (l1H, m), 2.65-3.51 (6H, m), 4.56-4.64 (1H,m), 6.54-7.56 (10H, m)

The following compounds were obtained in substantially the same manneras that of Example 7-1).

Example 7-2)

N-[(2RS,3SR)-3-Cyclohexyl-3-hydroxy-2-(2-hydroxyphenylmethyl)propionyl]-L-tryptophan

NMR (CD₃OD, δ): 0.75-2.00 (12H, m), 2.60-3.76 (6H, m), 4.64-4.77 (1H,m), 6.53-7.62 (10H, m)

Example 8-1)

N-[(2RS,3SR)-3-Cyclohexyl-3-hydroxy-2-(2-hydroxyphenyl)propionyl]-L-tryptophan

NMR (CD₃OD, δ): 0.85-1.95 (11H, m), 3.18-3.25 (2H, m), 3.93-4.30 (3H,m), 4.50-4.71 (1H, m), 6.69-7.59 (10H, m)

Example 8-2)

N-[(2RS,3RS)-3-Cyclohexyl-3-hydroxy-2-(2-hydroxyphenyl)propionyl]-L-tryptophan

NMR (CD₃OD, δ): 0.80-1.90 (11H, m), 3.17-3.23 (2H, m), 3.83-4.15 (3H,m), 4.69-4.81 (1H, m), 6.62-7.61 (10H, m)

Example 9-1)

N-[(2RS,3SR)-4-(2-Hydroxyphenyl)-2-{1-cyclohexyl-1-(hydroxy)methyl}butyryl]-L-tryptophan

NMR (CD₃OD, δ): 0.80-2.20 (11H, m), 2.20-2.70 (3H, m), 3.18-3.39 (5H,m), 5.00-5.04 (1H, m), 6.65-7.61 (10H, m)

Example 9-2)

N-[(2RS,3RS)-4-(2-Benzyloxyphenyl)-2-{1-cyclohexyl-1-(hydroxy)methyl}butyryl]-L-tryptophan

NMR (CDCl₃, δ): 0.80-2.00 (11H, m), 2.20-2.66 (3H, m), 4.75-4.85 (1H,m), 6.61-7.84 (10H, m)

Example 10

N-[(2RS,3SR)-3-Cyclohexyl-3-hydroxy-2-(2-methoxyphenylmethyl)propionyl]-L-tryptophan

NMR (CD₃OD, δ): 0.80-1.90 (11H, m), 2.54-3.54 (6H, m), 3.70 (1.5H, s),3.72 (1.5H, s), 4.48-4.61 (1H, m), 6.52-7.55 (10H, m)

Example 11

N-[2-(2-Carboxyphenylmethyl)-3-cyclohexyl-3-hydroxypropionyl]-L-tryptophan

NMR (CD₃OD, δ): 0.80-2.00 (11H, m), 2.84-3.09 (3H, m), 3.22-3.68 (3H,m), 4.49-4.62 (1H, m), 6.65-7.85 (10H, m)

Example 12-1)

N-[(2S,3S)-3-Cyclohexyl-2-(2-hydroxyphenyl)-3-hydroxypropionyl]-L-tryptophan

NMR (CD₃OD, δ): 0.80-1.80 (11H, m), 3.10-3.22 (2H, m), 4.01-4.11 (2H,m), 4.77 (1H, t, J=6.3 Hz), 6.62 (1H, s), 6.76-7.27 (8H, m), 7.40 (1H,d, J=7.8 Hz)

[α]_(D) ²⁴: 6.0° (C=0.25, CH₃OH)

Example 12-2)

N-[(2R,3R)-3-Cyclohexyl-2-(2-hydroxyphenyl)-3-hydroxypropionyl]-L-tryptophan

NMR (CD₃OD, δ): 0.80-1.80 (11H, m), 3.17-3.50 (2H, m), 3.97-4.11 (2H,m), 4.72 (1H, t, J=6.9 Hz), 6.64-6.78 (2H, m), 6.94-7.11 (6H, m), 7.31(1H, d, J=7.6 Hz), 7.58 (1H, d, J=7.9 Hz)

[α]_(D) ²⁵: 28.5° (C=0.2, CH₃OH)

Example 12-3)

N-[(2R,3R)-3-Cyclohexyl-2-(2-hydroxyphenyl)-3-hydroxypropionyl]-1-methyl-L-tryptophan

NMR (CD₃OD, δ): 0.80-1.80 (11H, m), 3.15-3.37 (2H, m), 3.67 (3H, s),3.98 (1H, d, J=8.4 Hz), 4.12 (1H, d, J=6.6 Hz), 4.67 (1H, t, J=6.6 Hz),6.65-7.17 (6H, m), 7.22 (1H, d, J=8.0 Hz), 7.59 (1H, d, J=7.7 Hz)

[α]_(D) ²⁹: 27.5° (C=0.20, CH₃OH)

Example 13-1)

To a solution of(2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-cyclohexyl-3-hydroxypropionicacid (100 mg), HCl.H-L-Trp-OMe (136 mg) and HOBT (55 mg) indimethylformamide (6 ml) was added WSCD (64 mg) under ice-bath cooling.After being stirred overnight at room temperature, the mixture waspoured into water (20 ml) and extracted with ethyl acetate (20 ml). Theorganic layer was washed with 5% hydrochloric acid solution, 1M aqueoussodium bicarbonate solution and brine, dried over magnesium sulfate, andconcentrated in vacuo to affordN-[(2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-cyclohexyl-3-hydroxypropionyl]-L-tryptophanemethyl ester (165 mg).

NMR (CDCl₃, δ) 0.95-1.76 (11H, m), 3.20 (1H, t, J=4 Hz), 3.28 (1H, t,J=4 Hz), 3.42 (1H, d, J=8 Hz), 3.62, 3.69 (1H, s), 3.75-3.92 (1H, m),4.80-4.98 (1H, m), 5.92 (1H, s), 5.97 (1H, s), 6.07-6.18 (1H, m),6.52-6.91 (4H, m), 7.00-7.22 (2H, m), 7.30-7.50 (2H, m), 7.95-8.10 (1H,m)

FAB MS m/z: 493 [M+H]⁺

The following compounds were obtained in substantially the same manneras that of Example 13-1).

Example 13-2)

N-[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-cyclohexyl-3-hydroxypropionyl]-L-1-naphthylalanineBenzyl Ester (170 mg)

NMR (CDCl₃, δ): 0.87-1.72 (11H, m), 3.33-3.60 (3H, m), 3.65-3.75 (1H,m), 3.75-3.85 (1H, m), 4.90-5.09 (3H, m), 5.90-6.00 (2H, m), 6.08 (1H,d, J=8 Hz), 6.45-6.70 (3H, m), 6.85-7.35 (7H, m), 7.40-7.55 (2H, m),7.70 (1H, t, J=8 Hz), 7.80-7.90 (1H, m), 7.95-8.05 (1H, m)

FAB MS m/z: 580 [M+H]⁺

Example 13-3)

N-[(2R,3R)-2-(3,4-Methylenedioxyphenyl)-3-cyclohexyl-3-hydroxypropionyl]-L-2-naphthylalanineethyl ester (129 mg)

NMR (CDCl₃, δ): 0.98-1.70 (14H, m), 3.21, 3.29 (1H, dd, J=8, 8 Hz), 3.45(1H, d, J=8 Hz), 3.78 (1H, d, J=6 Hz), 3.85 (1H, m), 4.12 (2H, m), 4.85(1H, q,

J=8 Hz), 5.87, 5.90 (2H, s), 6.12 (1H, d, J=8 Hz), 6.55-6.61 (2H, m),6.68 (1H, s), 7.17 (1H, d, J=8 Hz), 7.46 (3H, m), 7.69-7.80 (3H, m)

FAB MS m/z 518 [M+H]⁺

Example 13-4)

N-[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-cyclohexyl-3-hydroxypropionyl]-L-phenylalanineBenzyl Ester (143 mg)

NMR (CDCl₃, δ): 0.95-1.73 (11H, m), 2.92-3.13 (2H, m), 3.40-3.50 (1H,m), 3.68-3.75 (1H, m), 3.80-3.90 (1H, m), 4.79-4.93 (1H, m), 5.04-5.20(2H, m), 5.95 (3H, m), 6.57-6.77 (4H, m), 6.93 (1H, m), 7.03-7.37 (8H,m)

FAB MS m/z 530 [M+H]⁺

Example 13-5)

N-[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-cyclohexyl-3-hydroxypropionyl]-L-leucineBenzyl Ester (155 mg)

NMR (CDCl₃, δ): 0.80-0.90 (6H, m), 0.98-1.73 (14H, m), 3.45-3.55 (1H,m), 3.75-3.88 (2H, m), 4.60-4.70 (1H, m), 5.03-5.18 (2H, m), 5.95 (3H,m), 6.65-6.77 (3H, m), 7.23-7.35 (5H, m)

FAB MS m/z: 496 [M+H]⁺

Example 13-6)

N-[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-cyclohexyl-3-hydroxypropionyl]-L-phenylglycineMethyl Ester (156 mg)

NMR (CDCl₃, δ): 0.95-1.77 (11H, m), 3.55 (2H, m), 3.68, 3.72 (3H, s),3.85 (1H, m), 5.49 (1H, d, J=8 Hz), 5.97 (2H, m), 6.57-6.80 (4H, m),7.17 (1H, m), 7.30 (4H, m)

FAB MS m/z: 440 [M+H]⁺

Example 13-7)

N-[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-cyclohexyl-3-hydroxypropionyl]-L-Trp(Me)-OMe(185 mg)

NMR (CDCl₃, δ): 0.95-1.75 (11H, m), 3.10-3.29 (2H, m), 3.40-3.45 (1H,m), 3.63-3.72 (6H, m), 3.85-3.95 (2H, m), 4.78-4.92 (1H, m), 5.92, 5.98(2H, s), 6.09, 6.12 (1H, d, J=8 Hz), 6.28-6.75 (4H, m), 7.00-7.50 (4H,m)

FAB Ms m/z: 507 [M+H]⁺

Example 13-8)

N-[(2RS,3RS)-2-(2-Methoxyphenyl)-3-cyclohexyl-3-hydroxypropionyl]-L-tryptophanMethyl Ester (144 mg)

NMR (CDCl₃, δ): 0.90-1.32 (5H, m), 1.48-1.80 (6H, m), 3.10-3.30 (1H, m),3.58-3.60 (3H, s), 3.63, 3.70 (3H, s), 4.00-4.12 (3H, m), 4.82-4.92 (1H,m), 6.38, 6.42 (1H, d, J=7 Hz), 6.20-7.52 (9H, m), 7.77, 8.05 (1H, s)

FAB MS m/z: 555 [M+H]⁺

Example 13-9)

N-[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-tryptophanMethyl Ester (260 mg)

NMR (CDCl₃, δ): 0.76-0.86 (3H, m), 1.10-1.50 (6H, m), 3.12-3.30 (3H, m),3.62, 3.68 (3H, s), 4.00-4.12 (1H, m), 4.82-4.96 (1H, m), 5.92, 5.98(2H, s), 6.02-6.13 (1H, m), 6.53-6.92 (4H, m), 7.02-7.50 (4H, m), 8.00,8.08 (1H, s)

FAB MS m/z: 467 [M+H]⁺

Example 13-10)

N-[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyhexanoyl]-L-tryptophanMethyl Ester (172 mg)

NMR (CDCl₃, δ): 0.76-0.86 (3H, m), 1.12-1.40 (3H, m), 1.40-1.58 (1H, m),3.18-3.24 (2H, m), 3.28 (1H, t, J=7 Hz), 3.65, 3.70 (3H, s), 3.85-4.12(2H, m), 4.72-4.98 (1H, m), 5.92, 5.98 (2H, s), 6.02-6.15 (1H, m),6.52-6.90 (4H, m), 7.02-7.22 (2H, m), 7.30-7.48 (2H, m), 8.00, 8.08 (1H,s)

FAB MS m/z 453 [M+H]⁺

Example 13-11)

N-[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyoctanoyl]-L-tryptophanMethyl Ester (170 mg)

NMR (CDCl₃, δ): 0.80-0.88 (3H, m), 1.10-1.56 (8H, m), 3.18-3.24 (2H, m),3.28 (1H, t, J=7 Hz), 3.72, 3.78 (3H, s), 3.98-4.10 (1H, m), 4.80-4.96(1H, m), 5.92, 5.98 (2H, s), 6.02-6.12 (1H, m), 6.52-6.92 (4H, m),7.02-7.50 (4H, m), 7.96, 8.10 (1H, s)

FAB MS m/z: 481 [M+H]⁺

Example 13-12)

N-[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxy-4-ethylhexanoyl]-L-tryptophanMethyl Ester (168 mg)

NMR (CDCl₃, δ): 0.70-0.92 (7H, m), 1.15-1.54 (4H, m), 3.18-3.25 (1H, m),3.26-3.30 (1H, m), 3.42-3.48 (1H, dd, J=3, 8 Hz), 3.64, 3.68 (3H, s),3.80-4.25 (2H, m), 4.82-5.00 (1H, m), 5.92, 5.98 (2H, s), 6.03-6.18 (1H,m), 6.50-6.90 (4H, m), 7.02-7.55 (4H, m), 7.96, 8.08 (1H, s)

FAB MS m/z: 481 [M+H]⁺

Example 13-13)

N-[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxy-5-methylhexanoyl]-L-tryptophanMethyl Ester (196 mg)

NMR (CDCl₃, δ): 0.73-0.93 (6H, m), 1.20-1.30 (2H, m), 1.75-1.90 (1H, m),3.15 (1H, d, J=7 Hz), 3.14, 3.18 (3H, s), 3.75-3.95 (1H, m), 4.05-4.15(1H, m), 4.80-4.95 (1H, m), 5.92-5.98 (2H, s), 6.00-6.10 (1H, m),6.50-6.90 (4H, m), 7.00-7.50 (4H, m), 7.98, 8.06 (1H, s)

FAB MS m/z: 467 [M+H]⁺

Example 13-14)

N-[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxy-4-cyclohexylbutyryl]-L-tryptophanMethyl Ester (175 mg)

NMR (CDCl₃, δ): 0.55-1.30 (13H, m), 3.03 (1H, d, J=8 Hz), 3.21, 3.28(2H, t, J=7 Hz), 3.64, 3.6 (3H, s), 3.80-3.95 (1H, m), 4.05-4.20 (1H,m), 4.80-4.95 (1H, m), 5.92, 5.97 (2H, s), 6.02, 6.08 (1H, d, J=8 Hz),6.50-6.90 (4H, m), 7.00-7.40 (4H, m), 7.97, 8.04 (1H, s)

FAB MS m/z: 507 [M+H]⁺

Example 13-15)

N-[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyvaleryl]-L-tryptophanMethyl Ester (201 mg)

NMR (CDCl₃, δ): 0.88, 0.90 (3H, t, J=7 Hz), 1.15-1.40 (2H, m), 3.15-3.30(3H, m), 3.65, 3.68 (3H, s), 3.85-4.10 (2H, m), 4.80-4.95 (1H, m), 5.91,5.97 (2H, s), 6.02, 6.08 (1H, d, J=8 Hz), 6.50-6.93 (4H, m), 7.00-7.50(4H, m), 7.97, 8.06 (1H, s)

FAB MS m/z: 439 [M+H]⁺

Example 13-16)

N-[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxy-5,5-dimethylhexanoyl]-L-tryptophanMethyl Ester (193 mg)

NMR (CDCl₃, δ): 0.83, 0.86 (9H, s), 0.98-1.35 (2H, m), 3.10-3.35 (3H,m), 3.63, 3.68 (3H, s), 4.10-4.25 (2H, m), 4.80-4.95 (1H, m), 5.92, 5.98(2H, s), 6.08, 6.12 (1H, d, J=8 Hz), 6.55-6.95 (4H, m), 7.00-7.50 (4H,m), 7.98, 8.08 (1H, s)

FAB MS m/z: 481 [M+H]⁺

Example 13-17)

N-[(2RS,3RS)-3-Hydroxy-4-methyl-2-(3,4-methylenedioxyphenyl)valeryl]-L-tryptophanMethyl Ester (1.08 g)

NMR (CDCl₃, δ): 0.78-0.86 (3H, m), 0.90-0.96 (3H, m), 1.34-1.48 (1H, m),3.19-3.39 (3H, m), 3.66, 3.69 (total 3H, s), 3.72-3.76 (0.5H, m),3.87-3.98 (1.5H, m), 4.82-4.95 (1H, m), 5.92, 5.97 (total 2H, s), 6.08(0.5H, d, J=8 Hz), 6.12 (0.5H, d, J=8 Hz), 6.54-6.74 (3H, m), 6.92-7.22(3H, m), 7.29-7.38 (1.5H, m), 7.49 (0.5H, d, J=8 Hz), 7.99-8.04 (1H, brs)

Example 13-18)

N-[(2RS,3RS)-2-(1,4-Benzodioxan-6-yl)-3-hydroxyheptanoyl]-L-tryptophanMethyl Ester (241 mg)

NMR (CDCl₃, δ): 0.78-0.90 (3H, m), 1.10-1.48 (6H, m), 3.12-3.30 (3H, m),3.14, 3.16 (3H, s), 4.03-4.18 (1H, m), 4.20, 4.28 (4H, s), 4.82-4.99(1H, m), 6.08-6.25 (1H, m), 6.55-6.92 (3H, m), 7.00-7.50 (3H, m), 7.98,8.08 (1H, s)

FAB MS m/z: 481 [M+H]⁺

Example 13-19)

N-[(2RS,3RS)-2-(2-Naphthyl)-3-hydroxyheptanoyl]-L-tryptophan MethylEster (256 mg)

NMR (CDCl₃, δ): 0.75-0.82 (3H, m), 1.05-1.50 (6H, m), 3.05-3.30 (2H, m),3.48 (1H, d, J=8 Hz), 3.60-3.68 (1H, s), 4.04-4.18 (1H, m), 4.22-4.32(1H, m), 4.78-4.95 (1H, m), 5.99, 6.08 (1H, d, J=7 Hz), 6.12, 6.70 (1H,d, J=3 Hz), 6.80-7.30 (4H, m), 7.38-7.92 (8H, m)

FAB MS m/z: 473 [M+H]⁺

Example 13-20)

N-[(2RS,3RS)-2-(3,4-Dimethoxyphenyl)-3-hydroxyheptanoyl]-L-tryptophanMethyl Ester (244 mg)

NMR (CDCl₃, δ): 0.84 (3H, t, J=7 Hz), 1.18-1.45 (6H, m), 3.08, 3.15 (1H,d, J=4 Hz), 3.18-3.22 (1H, m), 3.25-3.32 (2H, m), 3.68, 3.70 (3H, s),3.71, 3.76 (3H, s), 3.86, 3.89 (3H, s), 4.18-4.30 (1H, m), 4.80-4.94(1H, m), 6.10, 6.18 (1H, d, J=8 Hz), 6.45-6.87 (3H, m), 6.96-7.46 (5H,m), 7.92, 8.05 (1H, s)

FAB MS m/z: 483 [M+H]⁺

Example 13-21)

N-[(2RS)-2-(3,4-Methylenedioxyphenyl)-3-phenylpropionyl]-L-tryptophanMethyl Ester (630 mg)

NMR (CDCl₃, δ): 2.86-2.97 (1H, m), 3.08-3.28 (2H, m), 3.39-3.53 (2H, m),3.59, 3.63 (total 3H, s), 4.80-4.93 (1H, m), 5.88-5.98 (3H, m),6.36-6.82 (4H, m), 6.98-7.07 (2H, m), 7.10-7.33 (7H, m), 7.90-8.00 (1H,m)

Example 13-22)

N-[(2RS,3RS)-3-Hydroxy-2-(3,4-methylenedioxyphenyl)-3-phenylbutyryl]-L-tryptophanMethyl Ester (150 mg)

NMR (CDCl₃, δ): 2.50-2.70 (2H, m), 3.19-3.30 (3H, m), 3.66, 3.69 (total3H, s), 3.75-3.85 (1H, m), 4.24-4.36 (1H, m), 4.85-4.97 (1H, m), 5.94,5.98 (total 2H, s), 6.07-6.22 (1H, m), 6.57-6.76 (3H, m),7.02-7.26 (7H,m), 7.30-7.50 (2H, m), 7.98-8.08 (1H, m)

Example 13-23)

N-[(2RS,3SR)-3-Hydroxy-2-(3,4-methylenedioxyphenyl)-3-(2-pyridyl)propionyl]-L-tryptophanMethyl Ester (50 mg)

NMR (CDCl₃, δ): 3.22-3.26 (2H, m), 3.66, 3.67 (total 3H, s), 3.86-3.89(1H, m), 4.57-4.68 (1H, m), 4.85-4.98 (1H, m), 5.38-5.47 (1H, m), 5.85,5.90 (total 2H, s), 6.38-6.70 (4H, m), 6.97-7.58 (7H, m), 7.96-8.10 (1H,m), 8.39-8.46 (1H, m)

Example 13-24)

N-[(2RS,3SR)-3-Hydroxy-2,3-bis(3,4-methylenedioxyphenyl)propionyl]-L-tryptophanMethyl Ester (438 mg)

NMR (CDCl₃, δ): 3.20-3.30 (2H, m), 3.40-3.48 (1H, m), 3.67, 3.70 (total3H, s), 4.37 (0.5H, d, J=3 Hz), 4.66 (0.5H, d, J=3 Hz), 4.87-5.03 (2H,m), 5.85-5.94 (4H, m), 6.06 (0.5H, d, J=8 Hz), 6.11 (0.5H, d, J=8 Hz),6.34-6.50 (1H, m), 6.52-6.87 (5H, m), 6.99-7.22 (2H, m), 7.29-7.49 (2H,m), 7.96-8.08 (2H, m)

Example 13-25)

N-[(2RS,3SR)-3-Hydroxy-2-(3,4-methylenedioxyphenyl)-3-(3,4,5-trimethoxyphenyl)propionyl]-L-tryptophanMethyl Ester (270 mg)

NMR (CDCl₃, δ): 3.22-3.29 (2H, m), 3.42-3.47 (1H, m), 3.66-3.79 (12H,m), 4.85-5.03 (2H, m), 5.89 (1H, s), 5.93 (1H, s), 6.06 (0.5H, d, J=8Hz), 6.12 (0.5H, d, J=8 Hz), 6.28 (1H, s), 6.37 (1H, s), 6.38 (0.5H, dd,J=1, 8 Hz), 6.47 (0.5H, dd, J=1, 8 Hz), 6.53-6.73 (3H, m), 6.98-7.21(3H, m), 7.29-7.48 (2H, m), 7.98-8.02 (0.5H, br), 8.08-8.12 (0.5H, br)

Example 13-26)

N-[(2RS,3SR)-3-Hydroxy-2-(3,4-methylenedioxyphenyl)-3-(4-methoxycarbonylphenyl)propionyl]-L-tryptophanMethyl Ester (195 mg)

NMR (CDCl₃, δ): 3.22-3.29 (2H, m), 3.44-3.49 (1H, m), 3.68, 3.70 (total3H, s), 3.87, 3.89 (total 3H, s), 4.68 (0.5H, d, J=3 Hz), 4.85-4.98 (1H,m), 4.94 (0.5H, d, J=3 Hz), 5.87-5.95 (2H, m), 6.02-6.10 (2H, m), 6.30(0.5H, dd, J=2, 9 Hz), 6.37 (0.5H, dd, J=2, 9 Hz), 6.50-6.74 (3H, m),6.98-7.48 (6H, m), 7.83 (1H, d, J=8 Hz), 7.88 (1H, d, J=8 Hz), 7.97-8.09(1H, m)

Example 13-27)

N-[(2RS,3SR)-3-Hydroxy-2-(3,4-methylenedioxyphenyl)-3-(4-biphenylyl)propionyl]-L-tryptophanMethyl Ester (293 mg)

NMR (CDCl₃, δ): 3.22-3.31 (2H, m), 3.52-3.58 (1H, m), 3.66, 3.70 (total3H, s), 4.38-4.43 (0.5H, br s), 4.80-5.18 (2.5H, m), 5.88-5.97 (2H, m),6.08-6.17 (1H, m), 6.38-6.50 (1H, m), 6.55-6.62 (2H, m), 6.67, 6.74(total 1H, s), 7.03-7.59 (13H, m), 7.95-8.03 (1H, m)

Example 13-28)

N-[(2RS,3SR)-3-Hydroxy-2-(3,4-methylenedioxyphenyl)-3-(2-n-butyl-1-tert-butoxycarbonyl-1H-imidazol-4-yl)propionyl]-L-triptophanMethyl Ester (130 mg)

NMR (CDCl₃, δ): 0.86-0.96 (3H, m), 1.27-1.40 (2H, m), 1.54, 1.59 (total9H, s), 1.56-1.68 (2H, m), 2.84-2.96 (2H, m), 3.20-3.29 (2H, m), 3.60(3H, s), 3.86-4.03 (1.5H, m), 4.50 (0.5H, d, J=7 Hz), 4.84-5.03 (1H, m),5.90, 5.95 (total 2H, s), 6.24-6.36 (1H, m), 6.58-6.69 (2H, m), 6.79(1H, s), 6.93-7.20 (3H, m), 7.27-7.50 (3H, m), 8.06-8.16 (1H, m)

Example 14-1)

To a solution ofN-[(2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-cyclohexyl-3-hydroxypropionyl]-L-tryptophanmethyl ester (160 mg) in MeOH (2 ml) was added 1M aqueous sodiumhydroxide solution (1 ml) at room temperature. After being stirred for 1hours at the same temperature, the mixture was concentrated in vacuo.The residue was dissolved in 1N hydrochloric acid (5 ml) and ethylacetate (10 ml) and the organic layer was washed with brine, dried overmagnesium sulfate, and concentrated in vacuo to giveN-[(2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-cyclohexyl-3-hydroxypropionyl]-L-tryptophan(150 mg).

NMR (CDCl₃, δ): 0.88-1.75 (11H, m), 3.18-3.25 (1H, m), 3.30 (1H, t, J=7Hz), 3.40-3.48 (1H, m), 3.85-3.96 (1H, m), 4.78-4.92 (1H, m), 5.90 (1H,m), 5.98 (1H, m), 6.37 (1H, t, J=8 Hz), 6.46-6.92 (4H, m), 7.00-7.55(4H, m), 8.14, 8.22 (1H, s)

FAB MS m/z: 479 [M+H]⁺

The following compounds were obtained in substantially the same manneras that of Example 14-1).

Example 14-2)

N-[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-cyclohexyl-3-hydroxypropionyl]-L-1-naphthylalanine(117 mg)

NMR (DMSO-d₆, δ): 0.90-1.65 (11H, m), 3.20-3.50 (2H, m),3.55-3.65 (1H,m), 3.70-3.80 (1H, m), 4.45-4.60 (1H, m), 5.94 (2H, s), 6.60-6.90 (3H,m), 7.05-7.15 (1H, m), 7.30-7.40 (1H, m), 7.40-7.60 (2H, m), 7.60-7.95(2H, m), 8.00-8.20 (1H, m), 8.30-8.40 (1H, d, J=8 Hz)

FAB MS m/z: 490 [M+H]⁺

Example 14-3)

N-[(2R,3R)-2-(3,4-Methylenedioxyphenyl)-3-cyclohexyl-3-hydroxypropionyl]-L-2-naphthylalanine(112 mg)

NMR (DMSO-d₆, δ): 0.75-1.65 (11H, m), 3.05-3.25 (2H, m), 3.16 (1H, d,J=8 Hz), 3.70-3.80 (1H, m), 4.53 (1H, q, J=7 Hz), 5.97 (2H, s), 6.74(2H, s), 6.89 (1H, s), 7.35-7.50 (3H, m), 7.75-7.90 (3H, m), 8.21 (1H,d, J=8 Hz), 7.71 (1H, s)

FAB MS m/z: 490 [M+H]⁺

Example 14-4)

N-[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-cyclohexyl-3-hydroxypropionyl]-L-phenylalanine(103 mg)

NMR (CDCl₃, δ): 0.95-1.71 (11H, m), 2.88-3.21 (2H, m), 3.47-3.57 (2H,m), 3.60-4.10 (1H, m), 4.60-4.80 (1H, m), 5.93, 5.98 (2H, s), 6.32-6.47(1H, m), 6.55-6.73 (3H, m), 6.82-6.85 (1H, m), 7.01-7.13 (2H, m),7.20-7.25 (1H, m)

FAB MS m/z: 440 [M+H]⁺

Example 14-5)

N-[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-cyclohexyl-3-hydroxypropionyl]-L-leucine(105 mg)

NMR (CDCl₃, δ): 0.85-0.94 (6H, m), 0.98-1.80 (14H, m), 3.47-3.68 (1H,m), 3.87-4.03 (1H, m), 4.35-4.57 (1H, m), 5.93 (2H, s), 6.30 (1H, m),6.63-6.93 (3H, m)

FAB MS m/z: 406 [M+H]⁺

Example 14-6)

N-[(2R,3R)-2-(3,4-Methylenedioxyphenyl)-3-cyclohexyl-3-hydroxypropionyl]-L-phenylglycine(111 mg)

NMR (DMSO-d₆, δ): 0.80-1.70 (11H, m), 3.77, 3.80 (3H, s), 5.23-5.30 (1H,m), 5.90-6.00 (2H, m), 6.70-6.95 (3H, m), 7.20-7.40 (5H, m), 8.50-8.65(1H, m)

FAB MS m/z: 426 [M+H]⁺

Example 14-7)

N-[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-cyclohexyl-3-hydroxypropionyl]-L-Trp(Me)-OH(165 mg)

NMR (CDCl₃, δ): 0.85-1.78 (11H, m), 3.10-3.30 (3H, m), 4.70-4.80 (1H,m), 3.60, 3.68 (3H, s), 3.83-3.98 (1H, m), 5.88, 5.92 (1H, s), 6.30-6.80(5H, m), 6.95-7.50 (4H, m)

FAB MS m/z: 493 [M+H]⁺

Example 14-8)

N-[(2RS,3RS)-2-(2-Methoxyphenyl)-3-cyclohexyl-3-hydroxypropionyl]-L-tryptophan(98 mg)

NMR (CDCl₃, δ): 0.85-1.20 (5H, m), 1.22-1.73 (6H, m), 3.22 (1H, d, J=7Hz), 3.28 (1H, t, J=7 Hz), 3.50, 3.53 (3H, s), 3.95-4.10 (1H, m),4.76-4.88 (1H, m), 6.40, 6.53 (1H, d, J=8 Hz), 6.46-7.56 (9H, m), 7.94,8.18 (1H, s)

FAB MS m/z: 465 [M+H]⁺

Example 14-9)

N-[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-tryptophan(220 mg)

NMR (CDCl₃, δ): 0.75-0.85 (3H, m), 1.06-1.50 (6H, m), 3.14-3.38 (3H, m),3.98-4.12 (1H, m), 4.78-4.92 (1H, m), 5.86-5.92 (1H, m), 5.94-5.98 (1H,m), 6.32, 6.40 (1H, d, J=7 Hz), 6.44-6.90 (4H, m), 6.98-7.52 (4H, m),8.20, 8.28 (1H, s)

FAB MS m/z: 453 [M+H]⁺

Example 14-10)

N-[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyhexanoyl]-L-tryptophan(130 mg)

NMR (CDCl₃, δ): 0.75-0.86 (3H, m), 1.10-1.30 (3H, m), 1.35-1.55 (1H, m),3.15-3.38 (3H, m), 4.00-4.18 (2H, m), 4.76-4.95 (1H, m), 5.88, 5.96 (1H,s), 6.32, 6.40 (1H, d, J=7 Hz), 6.45-6.60 (2H, m), 6.68-6.90 (2H, m),7.00-7.20 (2H, m), 7.30-7.52 (2H, m), 8.20, 8.28 (1H, s)

FAB MS m/z: 439 [M+H]⁺

Example 14-11)

N-[(2R3S,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyoctanoyl]-L-tryptophan(140 mg)

NMR (CDCl₃, δ): 0.78-0.86 (3H, m), 1.02-1.50 (8H, m), 3.10-3.30 (3H, m),4.00-4.12 (1H, m), 4.75-4.92 (1H, m), 5.85-5.96 (2H, m), 6.30-6.90 (4H,m), 6.96-7.52 (4H, m), 8.18, 8.28 (1H, s)

FAB MS m/z: 467 [M+H]⁺

Example 14-12)

N-[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxy-4-ethylhexanoyl]-L-tryptophan(143 mg)

NMR (CDCl₃, δ): 0.68-0.92 (7H, m), 1.05-1.50 (4H, m), 3.16-3.38 (2H, m),3.40-3.50 (1H, m), 4.15-4.30 (1H, m), 4.76-4.92 (1H, m), 5.87-5.97 (2H,m), 6.30, 6.39 (1H, d, J=8 Hz), 6.45-6.90 (4H, m), 7.00-7.54 (4H, m),8.12, 8.24 (1H, s)

FAB MS m/s 467 [M+H]⁺

Example 14-13)

N-[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxy-5-methylhexanoyl]-L-tryptophan(161 mg)

NMR (CDCl₃, δ): 0.65-0.95 (6H, m), 1.10-1.35 (2H, m), 1.65-1.85 (1H, m),3.00-3.35 (3H, m), 4.05-4.20 (1H, m), 4.70-4.90 (1H, m), 5.82, 5.83 (1H,s), 5.93, 5.94 (1H, s), 6.35-6.90 (5H, m), 6.95-7.55 (4H, m), 8.26, 8.35(1H, m)

FAB MS m/z: 453 [M+H]⁺

Example 14-14)

N-[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxy-4-cyclohexylbutyryl]-L-tryptophan(144 mg)

NMR (CDCl₃, δ): 0.50-1.75 (13H, m), 3.05-3.35 (3H, m), 4.10-4.25 (1H,m), 4.75-4.90 (1H, m), 5.82, 5.83 (1H, s), 5.92, 5.93 (1H, s), 6.35-6.90(5H, m), 6.95-7.53 (4H, m), 8.20, 8.30 (1H, s3)

FAB MS m/z: 493 [M+H]⁺

Example 14-15)

N-[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyvaleryl]-L-tryptophan(188 mg)

NMR (CDCl₃, δ): 0.75-0.90 (3H, m), 1.00-1.30 (2H, m), 3.10-3.30 (3H, m),3.90-4.05 (1H, m), 4.70-4.90 (1H, m), 5.80, 5.92 (2H, s), 6.35-6.90 (5H,m), 6.90-7.50 (4H, m), 8.29, 8.38 (1H, s)

FAB MS m/z 425 [M+H]⁺

Example 14-16)

N-[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxy-5,5-dimethylhexanoyl]-L-tryptophan(125 mg)

NMR (CDCl₃, δ): 0.79, 0.82 (9H, s), 1.00-1.35 (2H, m), 3.10-3.40 (3H,m), 4.10-4.25 (1H, m), 4.75-4.90 (1H, m), 5.88, 5.95 (2H, s), 6.27, 6.32(1H, d, J=7 Hz), 6.45-6.90 (4H, m), 7.00-7.55 (4H, m), 8.12, 8.19 (1H,s)

FAB MS m/z: 467 [M+H]⁺

Example 14-17)

N-[(2RS,3RS)-3-Hydroxy-4-methyl-2-(3,4-methylenedioxyphenyl)valeryl]-L-tryptophan(1.00 g)

NMR (CDCl₃, δ): 0.73 (1.5H, d, J=8 Hz), 0.80 (1.5H, d, J=8 Hz), 0.87(1.5H, d, J=7 Hz), 0.91 (1.5H, d, J=7 Hz), 1.29-1.45 (1H, m), 3.19-3.38(3H, m), 3.92 (0.5H, dd, J=4, 10 Hz), 3.99 (0.5H, dd, J=4, 10 Hz),4.78-4.88 (1H, m), 5.88 (1H, d, J=2 Hz), 5.96 (1H, s), 6.29 (0.5H, d,J=8 Hz), 6.35 (0.5H, d, J=8 Hz), 6.49 (0.5H, d, J=9 Hz), 6.58 (1.5H, d,J=8 Hz), 6.70 (1.5H, d, J=9 Hz), 6.90 (0.5H, d, J=1 Hz), 6.98-7.22 (2H,m), 7.27-7.35 (1.5H, m), 7.51 (0.5H, d, J=8 Hz), 8.10-8.14 (0.5H, br s),8.20-8.23 (0.5H, br s)

FAB MS: 439.0 [M+H]⁺

Example 14-18)

N-[(2RS,3RS)-2-(1,4-Benzodioxan-6-yl)-3-hydroxyheptanoyl]-L-tryptophan(148 mg)

NMR (CDCl₃, δ): 0.75-0.88 (3H, m), 1.10-1.42 (6H, m), 3.15-3.38 (3H, m),4.00-4.12 (1H, m), 4.15, 4.22 (4H, s), 4.38-4.96 (1H, m), 6.30-6.46 (1H,m), 6.50-6.90 (3H, m), 6.96-7.52 (3H, m), 8.15, 8.22 (1H, s)

FAB MS m/z: 467 [M+H]⁺

Example 14-19)

N-[(2RS,3RS)-2-(2-Naphthyl)-3-hydroxyheptanoyl]-L-tryptophan (218 mg)

NMR (CDCl₃, δ): 0.70-0.80 (3H, m), 1.03-1.48 (6H, m), 3.09-3.35 (2H, m),3.42, 3.48 (1H, d, J=8 Hz), 4.20-4.35 (1H, m), 4.72-4.92 (1H, m), 6.28,6.34 (1H, d, J=8 Hz), 6.40, 6.68 (1H, d, J=3 Hz), 6.75-7.30 (4H, m),7.44-7.60 (4H, m), 7.63-7.92 (4H, m)

FAB MS m/z: 459 [M+H]⁺

Example 14-20)

N-[(2RS,3RS)-2-(3,4-Dimethoxyphenyl)-3-hydroxyheptanoyl]-L-tryptophan(205 mg)

NMR (CDCl₃-CD₃OD, δ): 0.83 (3H, m), 1.15-1.42 (6H, m), 3.22 (1H, d, J=7Hz), 3.30 (2H, t, J=6 Hz), 3.68, 3.74 (3H, s), 3.85, 3.90 (3H, s),4.16-4.28 (1H, m), 4.72-4.88 (1H, m), 6.55-6.85 (3H, m), 6.93-7.50 (5H,m)

FAB MS m/z: 469 [M+H]⁺

Example 14-21)

N-[(2RS)-2-(3,4-Methylenedioxyphenyl)-3-phenylpropionyl]-L-tryptophan(522 mg)

NMR (CDCl₃, δ): 2.84-2.95 (1H, m), 3.10-3.28 (2H, m), 3.36-3.50 (2H, m),4.77-4.85 (1H, m), 5.86-5.98 (2H, m), 6.47-6.75 (4H, m), 6.95-7.07 (2H,m), 7.10-7.34 (7H, m), 7.99-8.05 (1H, br)

FAB MS: 457.3 [M+H]⁺

Example 14-22)

N-[(2RS,3RS)-3-Hydroxy-2-(3,4-methylenedioxyphenyl)-4-phenylbutyryl]-L-tryptophan(110 mg)

NMR (CDCl₃, δ): 2.42-2.68 (2H, m), 3.17-3.31 (3H, m), 4.22-4.35 (1H, m),4.78-4.90 (1H, m), 5.87-5.90 (1H, m), 5.95-5.99 (1H, m), 6.33-6.42 (1H,m), 6.50-6.76 (3H, m), 6.98-7.52 (9H, m), 8.06-8.09 0.5H, br s),8.12-8.16 (0.5H, br s)

FAB MS: 487.5 [M+H]⁺

Example 14-23)

N-[(2RS,3SR)-3-Hydroxy-2-(3,4-methylenedioxyphenyl)-3-(2-pyridyl)propionyl]-L-tryptophan(30 mg)

NMR (DMSO-d₆, δ): 2.82-3.08 (2H, m), 4.08 (1H, t, J=8 Hz), 4.28-4.36(1H, m), 5.06-5.19 (1H, m), 5.96, 5.97 (2H, s), 6.58-6.78 (2H, m),6.85-7.42 (9H, m), 8.16-8.20 (1H, m), 8.44-8.54 (1H, m)

FAB MS: 474.2 [M+H]⁺

Example 14-24)

N-[(2RS,3SR)-3-Hydroxy-2,3-bis(3,4-methylenedioxyphenyl)propionyl]-L-tryptophan(333 mg)

NMR (CDCl₃, δ): 3.15-3.44 (3H, m), 4.80-5.00 (2H, m), 5.78-5.93 (4H, m),6.30-6.42 (2H, m), 6.44-6.58 (4H, m), 6.68-6.88 (1H, m), 6.94-7.19 (2H,m), 7.24-7.50 (3H, m), 8.14-8.24 (1H, m)

FAB MS: 517 [M]⁺, 539.3 [M+Na]⁺

Example 14-25)

N-[(2RS,3SR)-3-Hydroxy-2-(3,4-methylenedioxyphenyl)-3-(3,4,5-trimethoxyphenyl)propionyl]-L-tryptophan(212 mg)

NMR (CDCl₃, δ): 3.22-3.43 (2H, m), 3.64 (3H, s), 3.71 (3H, s), 3.76,3.78 (total 3H, s), 4.83-5.03 (2H, m), 5.83 (1H, d, J=3 Hz), 5.91 (1H,d, J=3 Hz), 6.23-6.40 (4H, m), 6.50-6.58 (2H, m), 6.72 (0.5H, d, J=1Hz), 6.78 (0.5H, d, J=1 Hz), 6.96-7.18 (3H, m), 7.27-7.50 (2H, m),8.15-8.18 (0.5H, br s), 8.22-8.25 (0.5H, br s)

FAB MS: 545.4 [M-OH]⁺

Example 14-26)

N-[(2RS,3SR)-3-Hydroxy-2-(3,4-methylenedioxyphenyl)-3-(4-carboxyphenyl)propionyl]-L-tryptophan(150 mg)

NMR (DMSO-d₆, δ): 2.95-3.16 (3H, m), 3.87 (1H, dd, J=2, 10 Hz),4.48-4.58 (1H, m), 5.08 (1H, d, J=10 Hz), 5.87-5.93 (2H, m), 6.50-6.66(2H, m), 6.77-6.90 (2H, m), 6.96-7.10 (2H, m), 7.20-7.58 (4H, m),7.69-7.75 (2H, m), 8.22-8.30 (1H, m)

FAB MS: 517.2 [M+H]⁺

Example 14-27)

N-[(2RS,3SR)-3-Hydroxy-2-(3,4-methylenedioxyphenyl)-3-(4-biphenylyl)propionyl]-L-tryptophan(240 mg)

NMR (CDCl₃, δ): 3.22-3.32 (2H, m), 3.46-3.55 (1H, m),4.85-5.00 (1H, m),5.09-5.17 (1H, m), 5.82, 5.84 (total 1H, s), 5.89, 5.91 (total 1H, s),6.29-6.62 (4H, m), 6.73, 6.80 (total 1H, s), 6.99-7.54 (13H, m),8.07-8.11 (1H, brs)

FAB MS: 571.4 [M+Na]⁺

Example 15

Crude mixture of N-[(2R,3R)-, (2S,3S)-, (2R,3S)- and(2S,3R)-2-(3,4-methylenedioxyphenyl)-3-cyclohexyl-3-hydroxypropionyl]-L-tryptophan(429 mg) was purified by HPLC [Column: YMC ODS-AM, 250×20 mmI.D., 40-80%acetonitrile in 0.1% trifluoroacetic acid/water (120 minutes gradient),GILSON HPLC SYSTEM] to afford four fractions 109 mg (Isomer A), 96 mg(Isomer B), 94 mg (Isomer C) and 99 mg (Isomer D).

(Isomer A and B; retention time: 12.5 and 14.0 minutes, respectively):

N-[(2SR,3RS)-2-(3,4-Methylenedioxyphenyl)-3-cyclohexyl-3-hydroxypropionyl]-L-tryptophan

Isomer A

NMR (CDCl₃-CD₃OD, δ) 0.80-1.20 (6H, m), 1.50-1.88 (5H, m), 3.28 (2H, d,J=8 Hz), 3.52 (1H, d, J=7 Hz), 3.80-3.90 (1H, m), 4.88-4.97 (1H, m),5.97 (2H, s), 6.54 (1H, d, J=9 Hz), 6.65-6.88 (4H, m), 7.02-7.10 (1H,m), 7.17-7.22 (1H, m), 7.30-7.42 (2H, m), 8.14 (1H, s)

Isomer B

NMR (CDCl₃-CD₃OD, δ): 0.86-1.20 (6H, m), 1.48-1.78 (4H, m), 1.92-2.00(1H, m), 3.30 (1H, d, J=7 Hz), 3.40-3.48 (1H, m), 3.85-3.94 (1H, m),4.75-4.81 (1H, m), 5.93 (2H, s), 6.52 (1H, d, J=9 Hz), 6.60-6.72 (2H,m), 6.90 (2H, s), 7.04-7.56 (4H, m), 8.78 (1H, s)

(Isomer C; retention time: 15.0 minutes):

N-[(2R,3R)-2-(3,4-Methylenedioxyphenyl)-3-cyclohexyl-3-hydroxypropionyl]-L-tryptophan

Isomer C

NMR (CDCl₃-CD₃OD, δ): 0.88-1.15 (5H, m), 1.24-1.70 (6H, m), 3.22 (2H, d,J=7 Hz), 3.50 (1H, d, J=8 Hz), 3.96 (1H, dd, J=7 Hz), 4.85 (1H, m), 5.98(2H, s), 6.52-6.78 (5H, m), 7.04 (1H, t, J=8 Hz), 7.18 (1H, t, J=8 Hz),7.32 (1H, d, J=8 Hz), 7.38 (1H, d, J=8 Hz), 8.10 (1H, s)

FAB MS m/z: 479 [M+H]⁺

(Isomer D; retention time: 15.7 minutes)

N-[(2S,3S)-2-(3,4-Methylenedioxyphenyl)-3-cyclohexyl-3-hydroxypropionyl]-L-tryptophan

Isomer D

NMR (CDCl₃-CD₃OD, δ) 0.92-1.74 (11H, m), 3.20-3.45 (2H, m), 3.85 (1H, d,J=8 Hz), 4.72-4.80 (1H, m), 5.93 (2H, s), 6.50-6.92 (5H, m), 7.02-7.40(4H, m), 8.10 (1H, s)

Example 16

N-[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-Trp(Me)-OMe(1.33 g) was purified by silica gel column chromatography (eluent;hexane:ethyl acetate=3:1) to affordN-[(2R,3R)-2-(3,4-methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-Trp(Me)-OMe(1.39 g) andN-[(2S,3S)-2-(3,4-methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-Trp(Me)-OMe(1.35 g).

N-[(2R,3R)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-Trp(Me)-OMe

Rf: 0.56 (eluent; hexane:ethyl acetate=1:1)

NMR (CDCl₃, δ): 0.81 (3H, t, J=7 Hz), 1.10-1.50 (6H, m), 3.20 (1H, d,J=8.5 Hz), 3.28 (2H, t, J=7.5 Hz), 3.62 (3H, s), 4.05 (2H, m), 4.82 (1H,m), 5.90 (2H, s), 6.18 (1H, d, J=7.5 Hz), 6.52 (1H, d, J=8 Hz), 6.64(2H, m), 6.88 (1H, d, J=3 Hz), 7.10 (1H, t, J=8 Hz), 7.18 (1H, t, J=8Hz), 7.32 (1H, d, J=8 Hz), 7.48 (1H, d, J=8 Hz), 8.28 (1H, s)

FAB MS m/z: 467 [M+H]⁺

N-[(2S,3S)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-Trp(Me)-OMe

Rf: 0.42 (eluent; hexane:ethyl acetate=1:1)

NMR (CDCl₃, δ): 0.80 (3H, t, J=7 Hz), 1.10-1.50 (6H, m), 3.12-3.30 (3H,m), 3.68 (3H, s), 3.75-4.10 (2H, m), 4.92 (1H, m), 5.98 (2H, s), 6.05(1H, d, J=8 Hz), 6.59 (2H, d, J=7 Hz), 6.68-6.75 (2H, m), 7.04 (1H, t,J=8 Hz), 7.18 (1H, t, J=8 Hz), 7.32 (2H, d, J=8 Hz), 7.99 (1H, s)

FAB MS m/z: 467 [M+H]⁺

The following compounds were obtained in substantially the same manneras that of Example 14-1).

Example 17

N-[(2R,3R)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-Trp(Me)-OH(1.22 g)

NMR (CDCl₃, δ): 0.78 (3H, t, J=7 Hz), 1.04-1.47 (6H, m), 3.08-3.32 (3H,m), 4.00-4.10 (1H, m), 4.75-4.85 (1H, m), 5.80, 5.82 (2H, s), 6.43 (2H,d, J=8 Hz), 6.50-6.60 (2H, m), 6.80 (1H, s), 7.03 (1H, t, J=7 Hz), 7.13(1H, t, J=8 Hz), 7.23 (1H, d, J=7 Hz), 7.47 (1H, d, J=8 Hz), 8.32 (1H,s)

FAB MS m/z: 453 [M+H]⁺

Example 18

N-[(2S,3S)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-Trp(Me)-OH(1.17 g)

NMR (CDCl₃, δ): 0.78 (3H, t, J=7 Hz), 1.05-1.46 (6H, m), 3.10-3.23 (3H,m), 4.00-4.10 (1H, m), 4.80-4.90 (1H, m), 5.91 (2H, s), 6.50 (1H, d, J=8Hz), 6.58 (1H, d, J=8 Hz), 6.61-6.68 (3H, m), 6.98 (1H, t, J=8 Hz), 7.11(1H, t, J=8 Hz), 7.25 (1H, d, J=7 Hz), 7.30 (1H, d, J=8 Hz), 8.37 (1H,s)

FAB MS m/z: 453 [M+H]⁺

Example 19-1)

N-[(2R,3S)- and(2S,3R)-3-Hydroxy-2-(3,4-methylenedioxyphenyl)-3-phenylpropionyl]-L-tryptophanmethyl ester was obtained in substantially the same manner as that ofExample 13-1).

The stereoisomers were separated by silica gel column chromatography(eluent; n-hexane:ethyl acetate=2:1-3:2) to give more polar isomer (158mg) and less polar isomer (168 mg). The stereostructures of the morepolar and the less polar isomers were assigned as (2S,3R)- and(2R,3S)-configurations respectively.

More Polar Isomer

NMR (CDCl₃, δ): 3.20-3.26 (2H, m), 3.49-3.54 (1H, m), 3.70 (3H, s), 4.37(1H, d, J=4 Hz), 4.94-5.00 (1H, m), 5.08 (1H, dd, J=4, 10 Hz), 5.90-5.94(2H, m), 6.08 (1H, d, J=8 Hz), 6.35 (1H, dd, J=1, 8 Hz), 6.54-6.58 (3H,m), 6.99-7.34 (9H, m), 7.94-7.98 (1H, br)

Less Polar Isomer

NMR (CDCl₃, δ): 3.27 (2H, d, J=5 Hz), 3.48-3.51 (1H, m), 3.65 (3H, s),4.73 (1H, d, J=3 Hz), 4.86-4.93 (1H, m), 5.10 (1H, dd, J=3, 7 Hz),5.86-5.89 (2H, m), 6.12 (1H, d, J=8 Hz), 6.41 (1H, dd, J=1, 8 Hz), 6.55(1H, d, J=8 Hz), 6.60 (1H, d, J=1 Hz), 6.76 (1H, d, J=1 Hz), 7.18-7.24(7H, m), 7.34 (1H, d, J=8 Hz), 7.44 (1H, d, J=8 Hz), 7.99-8.03 (1H, br)

Example 19-2)

N-[(2R,3S)- and(2S,3R)-3-Hydroxy-2-(3,4-methylenedioxybenzyl)-3-phenylpropionyl]-L-tryptophanmethyl ester was obtained in substantially the same manner as that ofExample 13-1).

The stereoisomers were separated by silica gel column chromatography(eluent; n-hexane:ethyl acetate=3:1) to give more polar isomer (90 mg)and less polar isomer (205 mg). The stereostructures of the more polarand the less polar isomers were assigned as (2S,3R)- and(2R,3S)-configurations respectively.

More Polar Isomer

NMR (CDCl₃, δ): 2.50-2.61 (2H, m), 2.88-3.07 (2H, m), 3.13-3.22 (1H, m),3.57 (3H, s), 3.82 (1H, d, J=5 Hz), 4.76-4.86 (2H, m), 5.83-5.92 (3H,m), 6.52-6.58 (2H, m), 6.61 (1H, s), 6.67 (1H, d, J=8 Hz), 7.08 (1H, t,J=8 Hz), 7.17 (1H, t, J=8 Hz), 7.24-7.35 (7H, m), 7.98-8.03 (1H, br)

Less Polar Isomer

NMR (CDCl₃, δ): 2.50-2.58 (1H, m), 2.87-3.00 (3H, m), 3.14-3.21 (1H, m),3.55 (3H, s), 3.59 (1H, d, J=5 Hz), 4.72-4.85 (2H, m), 5.78-5.85 (1H,m),5.88 (2H, s), 6.23 (1H, d, J=2 Hz), 6.57-6.68 (3H, m), 7.03 (1H, d,J=8 Hz), 7.14 (1H, t, J=8 Hz), 7.23-7.38 (7H, m), 7.83-7.88 (1H, br)

The following compounds were obtained in substantially the same manneras that of Example 14-1)

Example 20-1)

N-[(2R,3S)-3-Hydroxy-2-(3,4-methylenedioxyphenyl)-3-phenylpropionyl]-L-tryptophan(124 mg)

NMR (CDCl₃, δ): 3.29 (2H, d, J=5 Hz), 4.88 (1H, dd, J=5, 14 Hz), 5.06(1H, d, J=9 Hz), 5.83 (2H, d, J=7 Hz), 6.23 (1H, d, J=8 Hz), 6.33 (1H,dd, J=1, 8 Hz), 6.47 (1H, d, J=8 Hz), 6.53 (1H, d, J=1 Hz), 6.81 (1H, d,J=1 Hz), 7.06-7.23 (7H, m), 7.30 (1H, d, J=8 Hz), 7.47 (1H, d, J=8 Hz),8.08-8.12 (1H, br)

FAB MS: 473.0 [M+H]⁺

Example 20-2)

N-[(2R,3S)-3-Hydroxy-2-(3,4-methylenedioxybenzyl)-3-phenylpropionyl]-L-tryptophan(165 mg)

NMR (CDCl₃, δ): 2.49-2.58 (1H, m), 2.69-2.80 (1H, m), 2.86-3.06 (2H, m),3.15-3.24 (1H, m), 4.74-4.80 (2H, m), 5.80 (2H, s), 5.88-5.96 (1H, m),6.43-6.60 (4H, m), 7.05 (1H, t, J=8 Hz), 7.18 (1H, t, J=8 Hz), 7.26-7.38(8H, m), 7.95-7.98 (1H, br s)

FAB MS 487 [M+H]⁺

Example 21-1)

N-[(2S,3R)-3-Hydroxy-2-(3,4-methylenedioxyphenyl)-3-phenylpropionyl]-L-tryptophan(119 mg)

NMR (CDCl₃, δ): 3.20 (1H, dd, J=6, 14 Hz), 3.27 (1H, dd, J=7, 14 Hz),3.43-3.51 (1H, m), 4.90-4.98 (1H, m), 5.07 (1H, d, J=9 Hz), 5.86, 5.90(total 2H, s), 6.28 (1H, dd, J=l, 8 Hz), 6.46-6.52 (2H, m), 6.56 (1H, d,J=1 Hz), 6.71 (1H, d, J=1 Hz), 6.93-7.00 (3H, m), 7.06-7.16 (4H, m),7.24 (1H, d, J=9 Hz), 7.29 (1H, d, J=9 Hz), 8.08-8.12 (1H, br)

FAB MS: 473.0 [M+H]⁺

Example 21-2)

N-[(2S,3R)-3-Hydroxy-2-(3,4-methylenedioxybenzyl)-3-phenylpropionyl]-L-tryptophan(81 mg)

NMR (CDCl₃, δ): 2.25-2.32 (1H, m), 2.50-2.59 (1H, m), 2.72-2.82 (1H, m),2.94-3.02 (1H, m),3.10-3.20 (1H, m), 4.70 (1H, d, J=8 Hz), 4.88-4.96(1H, m), 5.83, 5.86 (total 2H, s), 6.28 (1H, t, J=8 Hz), 6.46 (1H, dd,J=1, 9 Hz), 6.52 (1H, s), 6.59-6.67 (2H, m), 7.08 (1H, t, J=8 Hz),7.14-7.31 (9H, m), 8.08-8.12 (1H, br s)

FAB MS: 487 [M+H]⁺

Example 22

N-[(2RS,3SR)-3-Hydroxy-2-(3,4-methylenedioxyphenyl)-3-(4-carboxyphenyl)propionyl]-L-tryptophan(150 mg) was obtained from(2RS,3SR)-3-hydroxy-2-(3,4-methylenedioxyphenyl)-3-(4-carboxyphenyl)propionicacid in substantially the same manner as those of Examples 13-1) and14-1).

NMR (DMSO-d₆, δ): 2.95-3.16 (3H, m), 3.87 (1H, dd, J=2, 10 Hz),4.48-4.58 (1H, m), 5.08 (1H, d, J=10 Hz), 5.87-5.93 (2H, m), 6.50-6.66(2H, m), 6.77-6.90 (2H, m), 6.96-7.10 (2H, m), 7.20-7.58 (4H, m),7.69-7.75 (2H, m), 8.22-8.30 (1H, m)

FAB MS 517.2 [M+H]⁺

Example 23

A solution ofN-[(2RS,3SR)-3-hydroxy-2-(3,4-methylenedioxyphenyl)-3-(2-n-butyl-1-tert-butoxycarbonyl-1H-imidazol-4-yl)propionyl]-L-tryptophanmethyl ester (118 mg) in 1N aqueous sodium hydroxide solution (1.0 ml)and methanol (5.0 ml) was stirred at ambient temperature for 2 hours.The solution was acidified with 1N hydrochloric acid and the mixture wasdiluted with ethyl acetate followed by washing with brine. The organiclayer was dried and evaporated to afford crudeN-[(2RS,3SR)-3-hydroxy-2-(3,4-methylenedioxyphenyl)-3-(2-n-butyl-1-tert-butoxycarbonyl-1H-imidazol-4-yl)propionyl]-L-tryptophan.

A solution of the above crude product in trifluoroacetic acid (10 ml)was stirred at ambient temperature for 2 hours. The solvent was removedand to the residue was added 4N hydrogen chloride-ethyl acetate. Ethylacetate was evaporated in vacuo and then the residue was solidified withether. Resulting powder was collected by filtration and dried to affordN-[(2RS,3SR)-3-hydroxy-2-(3,4-methylenedioxyphenyl)-3-(2-n-butyl-1-tert-butoxycarbonyl-1H-imidazol-4-yl)propionyl]-L-tryptophan(68 mg).

FAB MS: 519.2 [M+H]⁺

Example 24

N-[(2RS,3SR)-3-Hydroxy-2-(3,4-methylenedioxyphenyl)-3-(2-n-butyl-1-tert-butyloxycarbonyl-1H-imidazol-4-yl)propionyl]-L-tryptophanwas obtained from(2RS,3SR)-3-hydroxy-2-(3,4-methylenedioxyphenyl)-3-(2-n-butyl-1H-imidazol-4-yl)propionicacid hydrochloride in substantially the same manner as those of Examples13-1) and 14-1).

FAB MS: 519.2 [M+H]⁺

The following compounds were obtained in substantially the same manneras that of Example 13-1).

Example 25-1)

[(2RS,3SR)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-1-Nal-OBzl(830 mg)

NMR (DMSO-d₆, δ): 0.82 (3H, t, J=7 Hz), 1.02-1.42 (6H, m), 3.15-3.55(3H, m), 3.83-4.00 (1H, m), 4.51-4.78 (2H, m), 4.85-5.12 (2H, m), 5.99,6.02 (2H, s), 6.60-6.92 (3H, m), 6.95-7.40 (6H, m), 7.48-8.16 (5H, m),8.51-8.65 (1H, m)

ESI-MS: 554 [M+H]

Example 25-2)

N^(α)-[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyheptanoyl]-3-(benzo[b]thiophen-3-yl)-L-alanineMethyl Ester

NMR (CDCl₃, δ): 0.83 (1.5H, t, J=7 Hz), 0.87 (1.5H, t, J=7 Hz),1.13-1.53 (6H, m), 3.18-3.32 (2H, m), 3.32-3.47 (1H, m), 3.63 (1.5H, s),3.68 (1.5H, s), 3.82 (0.5H, d, J=6 Hz), 3.87 (0.5H, d, J=6 Hz),4.01-4.13 (1H, m), 4.87-5.00 (1H, m), 5.90-6.00 (2H, m), 6.05 (0.5H, d,J=8 Hz), 6.12 (0.5H, d, J=8 Hz), 6.53-6.60 (1H, m), 6.62-7.08 (3H, m),7.28-7.42 (2H, m), 7.56-7.72 (1H, m), 7.79-7.78 (1H, m)

ESI-MS (m/z): 484 [M+H]

Example 25-3)

[(2R,3R)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-Trp(Me)-OMe

NMR (CDCl₃, δ): 0.82 (3H, t, J=7 Hz), 1.13-1.52 (6H, m), 3.1-3.28 (3H,m), 3.65 (3H, s), 3.71 (3H, s), 4.00-4.13 (2H, m), 4.78-4.87 (1H, m),5.92 (2H, s), 6.07 (1H, d, J=8 Hz), 6.52-6.58 (1H, m), 6.62-6.68 (2H,m), 6.72 (1H, s), 7.08 (1H, t, J=7 Hz), 7.27 (1H, d, J=6 Hz), 7.43 (1H,d, J=8 Hz)

ESI-MS (m/z): 481 [M+H]

Example 25-4)

[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-Trp(Me)-OMe

NMR (CDCl₃, δ): 0.78-0.83 (3H, m), 1.10-1.48 (9H, m), 3.10-3.30 (3H, m),3.63 (1.5H, s), 3.67 (1.5H, s), 3.83-4.17 (4H, m), 4.78-4.93 (1H, m),5.93 (1H, s), 5.97 (1H, s), 6.02-6.08 (1H, m), 6.39-6.80 (4H, m),6.98-7.46 (4H, m)

ESI-MS (m/z): 495 [M+H]

Example 25-5)

[(2R,3R)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-Trp(^(i)Pr)-OMe

NMR (CDCl₃, δ): 0.82 (3H, t, J=7 Hz), 1.11-1.45 (6H, m), 1.46 (3H, d,J=7 Hz), 1.48 (3H, d, J=7 Hz), 3.19 (1H, d, J=7 Hz), 3.26 (1H, d, J=6Hz), 3.63 (3H, s), 4.01-4.15 (2H, m), 4.59 (0.5H, q, J=7 Hz), 4.62(0.5H, q, J=7 Hz), 4.79-4.86 (1H, m), 5.92 (2H, s), 6.03 (1H, d, J=7Hz), 6.52 (1H, d, J=7 Hz), 6.62 (1H, s), 6.65 (1H, d, J=6 Hz), 6.91 (1H,s), 7.08 (1H, t, J=7 Hz), 7.45 (1H, d, J=7 Hz)

ESI-MS (m/z): 509 [M+H]

Example 25-6)

[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyheptanoyl]-DL-Trp(5-Me)-OMe

NMR (CDCl₃, δ): 0.78-0.84 (3H, m), 1.10-1.47 (6H, m), 2.42 (1.5H, s),2.46 (1.5H, s), 3.17-3.32 (3H, m), 3.66 (1.5H, s), 3.69 (1.5H, s),3.89-4.08 (2H, m), 4.80-4.89 (1H, m), 5.92 (1H, s), 5.95 (1H, s), 6.03(0.5H, d, J=7 Hz), 6.07 (0.5H, d, J=7 Hz), 6.52-6.86 (4H, m), 6.98-7.02(1H, m), 7.20-7.27 (2H, m), 7.88 (0.5H, s), 7.97 (0.5H, s)

ESI-MS (m/z): 481 [M+H]

Example 25-7)

[(2R,3R)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyheptanoyl]-DL-Trp(4-Me)-OMe

NMR (CDCl₃, δ): 0.82 (3H, t, J=7 Hz), 1.10-1.47 (6H, m), 2.63 (3H, s),3.18-3.29 (2H, m), 3.48 (0.5H, d, J=6 Hz), 3.53 (0.5H, d, J=6 Hz), 3.68(3H, s), 3.92-4.06 (2H, m), 4.78-4.85 (1H, m), 5.93 (2H, s), 6.02 (1H,d, J=7 Hz), 6.55 (1H, d, J=7 Hz), 6.63-6.68 (2H, m), 6.82-6.84 (2H, m),7.07 (1H, t, J=7 Hz), 7.17 (1H, d, J=7 Hz), 8.02 (1H, s)

ESI-MS (m/z): 481 [M+H]

Example 25-8)

[(2R,3R)-2-(3,4-methylenedioxyphenyl)-3-hydroxyheptanoyl]-DL-Trp(6-Me)-OMe

NMR (CDCl₃, δ): 0.80-0.88 (3H, m), 1.12-1.48 (6H, m), 2.45 (3H, s),3.17-3.27 (3H, m), 3.64 (3H, s), 4.00-4.08 (2H, m), 4.80-4.86 (1H, m),5.92 (2H, s), 6.08 (1H, d, J=8 Hz), 6.62-6.93 (4H, m), 7.12 (1H, s),7.34 (1H, d, J=7 Hz), 7.91 (1H, s)

ESI-MS (m/z) 481 [M+H]

Example 25-9)

[(2R,3R)-2-(3,4-methylenedioxyphenyl)-3-hydroxyheptanoyl]-DL-Trp(7-Me)-OMe

NMR (CDCl₃, δ): 0.83 (3H, t, J=7 Hz), 1.16-1.47 (6H, m), 2.47 (3H, s),3.19-3.30 (3H, m), 3.65 (3H, s), 4.00-4.08 (2H, m), 4.80-4.87 (1H, m),5.92 (2H, s), 6.08 (1H, d, J=7 Hz), 6.53-6.66 (3H, m), 6.91-7.06 (3H,m), 7.31 (1H, d, J=6 Hz), 7.97 (1H, s)

ESI-MS (m/z) 481 [M+H]

Example 25-10)

N^(α)-[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyheptanoyl]-DL-7-azatryptophanMethyl Ester

NMR (CDCl₃, δ): 0.77-0.84 (3H, m), 1.12-1.50 (6H, m), 3.18-3.37 (3H, m),3.67 (1.5H, s), 3.68 (1.5H, s), 3.95-4.18 (2H, m), 4.88-4.98 (1H, m),5.90-5.98 (2H, m), 6.32-7.04 (6H, m), 7.63 (0.5H, d, J=7 Hz), 7.80(0.5H, d, J=7 Hz), 8.21-8.26 (1H, m), 9.60 (1H, s)

ESI-MS (m/z): 468 [M+H]

Example 25-11)

[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyheptanol]-L-Trp(CHO)-OBzl(248 mg)

NMR (CDCl₃, δ): 0.81, 0.84 (3H, t, J=7 Hz), 1.10-1.48 (6H, m), 3.14-3.27(3H, m), 3.66-3.95 (1H, m), 4.02-4.13 (1H, m), 4.88-5.20 (3H, m),5.93-5.98 (2H, s), 6.12-6.18 (1H, d, J=8 Hz), 6.53-6.75 (3H, m),7.18-7.42 (5H, m), 8.28-8.72 (1H, m)

ESI-MS: 571 [M+H]

Example 25-12)

[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-Trp(COOMe)-OBzl(268 mg)

NMR (CDCl₃, δ): 0.79, 0.82 (3H, t, J=7 Hz), 1.07-1.50 (6H, m), 3.09,3.25 (3H, m), 4.00 (3H, s), 4.02-4.12 (1H, m), 4.88-5.03 (1H, m), 5.04,5.09 (2H, s), 5.88-5.96 (2H, m), 6.03-6.15 (1H, m), 6.49-6.68 (3H, m),7.01-7.46 (10H, m), 8.08-8.19 (1H, m)

ESI-MS: 601 [M+H]

Example 25-13)

[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-Trp(CH₂CO₂Et)-OBzl

NMR (CDCl₃, δ): 0.78 (1.5H, t, J=7 Hz), 0.82 (1.5H, t, J=7 Hz),1.09-1.46 (8H, m), 1.26 (3H, t, J=8 Hz), 3.12-3.32 (3H, m), 3.96-4.08(1H, m), 4.19 (2H, q, J=8 Hz), 4.61 (1H, s), 4.68 (1H, s), 4.87-5.02(1H, m), 5.03-5.12 (2H, m), 5.88-5.98 (2H, m), 6.13-6.74 (5H, m),6.98-7.48 (8H, m)

ESI-MS (m/z): 629 [M+H]

Example 25-14)

[(2R,3R)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-Trp(CH₂CONMe₂)-OMe

NMR (CDCl₃, δ): 0.80 (3H, t, J=7 Hz), 1.12-1.47 (6H, m), 2.98 (3H, s),3.06 (3H, s), 3.21-3.37 (3H, m), 3.67 (3H, s), 3.95-4.08 (2H, m),4.82-4.90 (3H, m), 5.91 (2H, s), 6.48 (1H, d, J=7 Hz), 6.57-6.67 (2H,m), 6.72 (1H, s), 6.90 (1H, s), 7.07-7.13 (1H, m), 7.18-7.20 (2H, m),7.48 (1H, d, J=7 Hz)

ESI-MS (m/z): 552 [M+H]

Example 25-15)

[(2R,3R)-3-Hydroxy-2-(3,4-methylenedioxyphenyl)-heptanoyl]-L-Trp(CH₂CH₂CO₂Et)-OMe

NMR (CDCl₃, δ): 0.83 (3H, t, J=8 Hz), 1.17-1.31 (6H, m), 1.20 (3H, t,J=8 Hz), 2.77 (2H, t, J=8 Hz), 3.22-3.28 (3H, m), 3.67 (3H, s),4.04-4.14 (4H, m), 4.38 (2H, t, J=8 Hz), 4.82 (1H, dd, J=6, 14 Hz), 5.94(2H, s), 6.11 (1H, d, J=8 Hz), 6.54-6.58 (1H, m), 6.64-6.67 (2H, m),6.87 (1H, s), 7.09 (1H, t, J=8 Hz), 7.21 (1H, dd, J=6, 7 Hz), 7.26-7.32(1H, m), 7.44 (1H, d, J=8 Hz)

ESI-MS: 567 [M+H]

Example 25-16)

[3-(1-t-Butoxycarbonyl-2-pentylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-Trp(CH₂CO₂^(t)Bu)-OBzl was obtained according to a similar manner to that ofExample 25-27).

NMR (CDCl₃, δ): 0.85-0.92 (3H, m), 1.24-1.38 (4H, m), 1.42 (9H, s), 1.50(4.5H, s), 1.53 (4.5H, s), 1.55-1.72 (2H, m), 2.77-2.97 (3H, m),3.08-3.32 (3H, m), 3.73-3.80 (1H, m), 4.49 (1H, s), 4.56 (1H, s),4.86-4.93 (1H, m), 4.95 (1H, s), 5.00 (1H, s), 5.87-5.97 (2H, m),6.13-7.43 (15H, m)

ESI-MS (m/z): 821 [M+H]

The following compounds were obtained in substantially the same manneras that of Example 13-1).

Example 25-17)

N^(α)-[3-Hydroxy-3,3-di(2-pyridyl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-tryptophanMethyl Ester

NMR (CDCl₃, δ): 2.98-3.09 (1H, m), 3.13-3.18 (1H, m), 3.47, 3.57 (total3H, s), 4.69-4.80 (1H, m), 5.22 (1H, d, J=8 Hz), 5.81-5.88 (2H, m),6.39-6.68 (3H, m), 6.77-6.84 (2H, m), 6.92-7.76 (9H, m), 7.94-8.09 (2H,m), 8.36 (1H, t, J=6 Hz), 8.43-8.47 (1H, br s)

ESI-MS: 565 [M+H]

Example 25-18)

N^(α)-[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-cyclopropyl-3-hydroxypropionyl]-L-tryptophanMethyl Ester

NMR (CDCl₃, δ): −0.10-0.02 (1H, m), 0.15-0.45 (3H, m), 0.62-0.82 (1H,m), 3.20-3.26 (1H, m), 3.30 (1H, t, J=6 Hz), 3.33-3.50 (2H, m), 3.67(1.5H, s), 3.70 (1.5H, s), 3.80-3.92 (1H, m), 4.87-4.98 (1H, m), 5.92(1H, s), 5.97 (1H, s), 6.18 (0.5H, d, J=7 Hz), 6.27 (0.5H, d, J=7 Hz),6.60-7.50 (8H, m), 8.01 (0.5H, s), 8.09 (0.5H, s)

ESI-MS (m/z): 451 [M+H]

Example 25-19)

N^(α)-[(2RS,3RS)-3-Hydroxy-3-(2-biphenylyl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-tryptophanMethyl Ester

NMR (CDCl₃, δ): 3.13-3.22 (3H, m), 3.42-3.56 (2H, m), 3.60 (1.5H, s),3.67 (1.5H, s), 4.63 (0.5H, d, J=5 Hz), 4.78-4.87 (1H, m), 5.06 (0.5H,d, J=6 Hz), 5.26-5.33 (1H, m), 5.85 (1H, d, J=4 Hz), 5.88-5.95 (2H, m),6.00 (1H, dd, J=2, 8 Hz), 6.11 (1H, s), 6.42 (1H, d, J=8 Hz), 6.47(0.5H, d, J=2 Hz), 6.61 (0.5H, d, J=2 Hz), 6.92-7.40 (10H, m), 7.60(0.5H, d, J=8 Hz), 7.69 (0.5H, d, J=8 Hz), 7.83-7.86 (0.5H, br s),7.97-8.00 (0.5H, br s)

Example 25-20)

[(2R,3R)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyoctanoyl]-L-Trp-OMe (248mg) as a less polar isomer was obtained according to a similar manner tothat of Example 13-1) by using silica gel column chromatography(hexane:AcOEt=1:1).

Rf: 0.51 (silica gel, hexane:AcOEt=1:1)

NMR (CDCl₃, δ): 0.82 (3H, t, J=7 Hz), 1.08-1.52 (8H, m), 3.20 (1H, d,J=8 Hz), 3.28 (2H, t, J=7 Hz), 3.65 (3H, s), 4.00-4.08 (1H, m),4.81-4.89 (1H, m), 5.92 (2H, s), 6.09 (1H, d, J=9 Hz), 6.54 (1H, d, J=8Hz), 6.65 (1H, s), 6.67 (1H, d, J=9 Hz), 6.91 (1H, d, J=3 Hz), 7.11 (1H,t, J=7 Hz), 7.20 (1H, t, J=7 Hz), 7.34 (1H, d, J=9 Hz), 7.48 (1H, d, J=9Hz), 8.07 (1H, s)

ESI-MS: 481 [M+H]

The following compounds were obtained in substantially the same manneras that of Example 13-1).

Example 25-21)

[(2RS,3SR)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyoctanoyl]-L-Trp(CH₂COOEt)-OBzl(448 mg)

NMR (CDCl₃, δ): 0.84, 0.87 (3H, t, J=7 Hz), 1.25 (1H, t, J=8 Hz),1.05-1.48 (8H, m), 3.10-3.32 (3H, m), 3.78-4.08 (2H, m), 4.20 (1H, q,J=8 Hz), 4.62 (2H, dd, J=2, 15 Hz), 4.85-5.01 (1H, m), 5.02-5.13 (2H,m), 5.86-5.99 (2H, m), 6.15-6.55 (2H, m), 6.57-6.75 (3H, m), 6.98-7.48(9H, m)

ESI-MS: 643 [M+H]

Example 25-22)

[(2RS,3SR)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyoctanoyl]-L-1-Nal-OBzl(532mg)

NMR (DMSO-d₆, δ): 0.82 (3H, t, J=7 Hz), 0.93-1.40 (8H, m), 3.20-3.53(3H, m), 3.82-3.96 (1H, m), 4.55-4.76 (2H, m), 4.82-5.10 (2H, m), 5.97,6.00 (2H, s), 6.63-6.88 (3H, m), 6.98-7.05 (1H, m), 7.12-7.38 (5H, m),7.45-7.60 (2H, m), 7.68-8.13 (3H, m), 8.54-8.62 (1H, m)

ESI-MS: 568 [M+H]

Example 25-23)

[(2R,3R)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyoctanoyl]-L-Trp(CH₂COOEt)-NHSO₂CH₃(170 mg) as a less polar isomer was obtained according to a similarmanner to that of Example 13-1) by using silica gel thin layerchromatography (10%-MeOH in CHCl₃).

Rf: 0.50 (10% MeOH in CHCl₃)

NMR (DMSO-d₃, δ): 0.80 (3H, t, J=7 Hz), 0.98-1.42 (8H, m), 1.20 (3H, t,J=7 Hz), 2.98-3.18 (2H, m), 3.01 (3H, s), 3.32-3.48 (1H, m), 3.87-4.00(1H, m), 4.15 (2H, q, J=8 Hz), 4.53-4.66 (1H, m), 4.72-4.87 (1H, m),5.02 (2H, m), 5.97 (2H, s), 6.72 (1H, d, J=7 Hz), 6.80 (1H, d, J=7 Hz),6.86 (1H, s), 6.89-7.25 (3H, m), 7.32 (1H, d, J=7 Hz), 7.63 (1H, d, J=7Hz), 8.28 (1H, d, J=7 Hz)

ESI-MS: 630 [M+H]

Example 25-24)

To a solution of3-(1-tert-butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionicacid (250 mg), L-tryptophan benzyl ester hydrochloride (209 mg) andtriethylamine (128 mg) in N,N-dimethylformamide (5 ml) was addeddiphenylphosphoryl azide (198 mg) and the mixture was stirred at ambienttemperature for 5.5 hours. The resulting mixture was diluted with ethylacetate and the organic layer was washed successively with 0.5N hydrogenchloride aqueous solution, saturated sodium bicarbonate aqueous solutionand brine. Drying, filtering and removal of the solvents afforded acrude product. The crude product was chromatographed on silica gel(eluent; n-hexane:ethyl acetate=1:2) to give[3-(1-tert-butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-tryptophanbenzyl ester (125 mg) as a yellow oil.

Rf: 0.47 (benzene:ethyl acetate:acetic acid=20:20:1)

ESI-MS: 693 [M+H]

The following compounds were obtained in substantially the same manneras that of Example 25-27).

Example 25-25)

N^(α)-[3-(1-tert-Butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-tryptophanEthyl Ester

NMR (CDCl₃, δ): 0.88-0.96 (3H, m), 1.04-1.18 (3H, m), 1.33-1.41 (2H, m),1.52, 1.56 (total 9H, s), 1.58-1.68 (2H, m), 2.78-2.98 (3H, m),3.15-3.30 (3H, m), 3.74-3.80 (1H, m), 3.95-4.16 (3H, m), 4.80-4.89 (1H,m), 5.90-5.97 (2H, m), 6.12-6.18 (1H, m), 6.65-6.70 (2H, m), 6.78-6.95(2H, m), 6.99-7.19 (2H, m), 7.28-7.49 (2H, m), 7.94-8.03 (1H, m)

ESI-MS: 631 [M+H]

Example 25-26)

N-[(2RS)-3-(1-tert-Butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-3-(1-naphthyl)alaninebenzyl ester (2R:2S=1:4)

NMR (CDCl₃, δ): 0.95 (3H, t, J=8 Hz), 1.30-1.42 (2H, m), 1.48, 1.56(total 9H, s), 1.60-1.70 (2H, m), 2.79-2.98 (3H, m), 3.20-3.32 (2H, m),3.40-3.57 (2H, m), 3.80 (1H, t, J=8 Hz), 4.83 (1H, d, J=11 Hz), 4.91(1H, d, J=11 Hz), 4.92-5.00 (1H, rn), 5.89-5.96 (2H, m), 6.29 (1H, d,J=8 Hz), 6.63-6.70 (2H, m), 6.82-7.07 (4H, m), 7.19-7.31 (4H, m),7.42-7.53 (2H, m), 7.66-7.71 (1H, m), 7.79-7.85 (1H, m), 8.10 (1H, d,J=8 Hz)

ESI-MS: 704 [M+H]

Example 25-27)

To a solution of(2RS)-3-(1-tert-butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionicacid (2R:2S=1:4, 250 mg) and HCl.H-L-Trp(CH₂CO₂Et)-OBzl (250 mg) indichloromethane (8 ml) was added portionwise water soluble carbodiimide(WSCD) (112 mg) at 0° C. and the mixture was stirred at ambienttemperature for 2 hours. The resulting solution was diluted withdichloromethane followed by washing successively with saturated ammoniumchloride aqueous solution and saturated sodium bicarbonate aqueoussolution. Drying, filtering and removal of the solvents afforded a crudeproduct. The crude product was chromatographed on silica gel (eluent;n-hexane:ethyl acetate=1:1) to give[(2RS)-3-(1-tert-butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-Trp(CH₂CO₂Et)-OBzl(2R:2S=1:4) (305 mg) as a white amorphous powder.

NMR (CDCl₃, δ): 0.93 (3H, t, J=8 Hz), 1.24 (3H, t, J=8 Hz), 1.32-1.42(2H, m), 1.53, 1.58 (total 9H, s), 1.60-1.70 (2H, m), 2.80-2.97 (3H, m),3.08-3.17 (1H, m), 3.20-3.31 (2H, m), 3.79 (1H, t, J=8 Hz), 4.18 (2H, q,J=8 Hz), 4.57, 4.66 (total 2H, s), 4.87-4.97 (1H, m), 4.96, 5.01 (total2H, s), 5.88-5.97 (2H, m), 6.17-6.23 (1H, m), 6.48-6.93 (3H, m),7.04-7.34 (10H, m), 7.42 (1H, d, J=8 Hz)

ESI-MS: 779 [M+H]

The following compounds were obtained in substantially the same manneras that of Example 25-27).

Example 25-28)

[(2RS)-3-(1-tert-Butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-Trp(CH₂CH₂CO₂Et)-OBzl(2R:2S=1:4)

NMR (CDCl₃, δ): 0.89-0.95 (3H, m), 1.16-1.23 (3H, m), 1.30-1.42 (2H, m),1.53, 1.56 (total 9H, s), 1.57-1.69 (2H, m), 2.60-2.69 (2H, m),2.80-2.97 (3H, m), 3.06-3.32 (3H, m), 3.80 (1H, t, J=8 Hz), 4.06-4.17(3H, m), 4.27 (1H, t, J=7 Hz), 4.85-4.97 (1H, m), 4.96, 5.02 (total 2H,s), 5.87-5.97 (2H, m), 6.18-6.25 (1H, m), 6.57-6.67 (2H, m), 6.72-6.93(2H, m), 7.02-7.12 (2H, m), 7.16-7.35 (7H, m), 7.42 (1H, d, J=8 Hz)

ESI-MS 793 [M+H]

Example 25-29)

[(2RS)-3-(1-tert-Butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-Trp(Me)-OBzl(2R:2S=1:4)

NMR (CDCl₃, δ): 0.88-0.96 (3H, m), 1.30-1.44 (2H, m), 1.52, 1.58 (total9H, s), 1.60-1.72 (2H, m), 2.80-2.97 (3H, m), 3.07-3.32 (3H, m), 3.56,3.62 (total 3H, s), 3.74-3.81 (1H, m), 4.86-4.93 (1H, m), 4.97, 5.03(total 2H, s), 5.88-6.05 (2H, m), 6.12-6.19 (1H, m), 6.59-6.67 (2H, m),6.72-7.33 (11H, m), 7.42 (1H, d, J=8 Hz)

ESI-MS: 707 [M+H]

Example 25-30)

[(2RS)-3-(1-tert-Butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-Trp(CH₂CO₂Bzl)-OBzl(2R:2S=1:4)

NMR (CDCl₃, δ): 0.88-0.95 (3H, m), 1.30-1.40 (2H, m), 1.53, 1.62 (total9H, s), 1.59-1.69 (2H, m), 2.78-2.96 (3H, m), 3.09-3.30 (3H, m),3.74-3.80 (1H, m), 4.60, 4.69 (total 2H, s), 4.86-5.00 (3H, m), 5.16(2H, s), 5.86-5.89 (2H, m), 6.25 (1H, d, J=8 Hz), 6.48 (1H, s),6.58-6.68 (2H, m), 6.78, 6.82 (total 1H, s), 6.88, 6.90 (total 1H, s),7.06-7.35 (13H, m), 7.44 (1H, d, J=8 Hz)

ESI-MS: 841 [M+H]

Example 25-31)

[(2RS)-3-(1-tert-Butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-Trp(CH₂CO₂^(t)Bu)-OBzl (2R:2S=1:4)

NMR (CDCl₃, δ): 0.89-0.96 (3H, m), 1.32-1.40 (2H, m), 1.45, 1.57 (total9H, s), 1.55, 1.63 (total 9H, s), 1.64-1.70 (2H, m), 2.84-2.97 (3H, m),3.09-3.30 (3H, m), 3.75-3.80 (1H, m), 4.47, 4.56 (total 2H, s),4.86-4.95 (1H, m), 4.96, 5.02 (total 2H, s), 5.87-5.96 (2H, m),6.13-6.22 (1H, m), 6.50-6.90 (5H, m), 7.05-7.42 (4H, m)

ESI-MS: 807 [M+H]

Example 25-32)

[(2RS)-3-(1-tert-Butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-Trp(Et)-OBzl(2R:2S=1:4)

Rf: 0.75 (10% methanol in chloroform)

Example 25-33)

N^(α)-[3-(1-Triphenylmethylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-tryptophanBenzyl Ester

NMR (CDCl₃, δ): 2.85-2.94 (1H, m), 3.13-3.30 (3H, m), 3.70-3.80 (1H, m),4.87-4.96 (1H, m), 4.95, 5.00 (total 2H, s), 5.89, 5.93 (total 2H, s),6.24-6.47 (2H, m), 6.53-6.75 (3H, m), 6.97-7.00 (6H, m), 7.07-7.32 (20H,m), 7.87-7.95 (1H, m)

ESI-MS: 779 [M+H]

Example 25-34)

N^(α)-[3-(1-Methylimidazol-5-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-tryptophanBenzyl Ester

NMR (CDCl₃, δ): 2.78-2.88 (1H, m), 3.19-3.26 (2H, m), 3.36-3.50 (4H, m),4.83-4.92 (1H, m), 5.05, 5.08 (total 2H, s), 5.90-5.96 (2H, m),6.01-6.07 (1H, m), 6.38-6.40 (1H, m), 6.56-6.73 (4H, m), 6.98-7.40 (11H,m), 8.27-8.30 (1H, br)

ESI-MS: 551 [M+H]

Example 25-35)

N^(α)-[3-(1-t-Butoxycarbonyl-2-ethylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-tryptophanbenzyl ester

NMR (CDCl₃, δ): 1.22-1.30 (3H, m), 1.52 (4.5H, s), 1.55 (4.5H, s),2.78-2.99 (3H, m), 3.10-3.33 (3H, m), 3.74-3.80 (1H, m), 4.85-5.01 (3H,m), 5.88-5.94 (2H, m), 6.18-6.24 (1H, m), 6.60-7.33 (13H, m), 7.45 (1H,d, J=7 Hz), 7.90 (0.5H, s), 7.98 (0.5H, s)

ESI-MS (m/z): 665 [M+H]

Example 25-36)

N^(α)-[(2RS)-3-(1-tert-Butoxycarbonyl-2-n-propylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-tryptophanBenzyl Ester (2R:2S=1:4)

NMR (CDCl₃, δ): 0.97 (3H, t, J=8 Hz), 1.53, 1.56 (total 9H, s),1.65-1.75 (2H, m), 2.79-2.98 (3H, m), 3.02-3.31 (3H, m), 3.79 (1H, t,J=9 Hz), 4.87-4.95 (1H, m), 4.96, 5.02 (total 2H, s), 5.88-5.95 (2H, m),6.20 (1H, d, J=8 Hz), 6.60-6.70 (2H, m), 6.79-6.95 (2H, m), 7.03-7.20(3H, m), 7.26-7.35 (5H, m), 7.45 (1H, d, J=8 Hz), 7.95-7.99 (1H, br s)

ESI-MS: 679 [M+H]

Example 25-37)

N^(α)-[3-(1-t-Butoxycarbonyl-2-pentylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-tryptophanBenzyl Ester

NMR (CDCl₃, δ): 0.87-0.93 (3H, m), 1.23-1.38 (4H, m), 1.50 (4.5H, s),1.54 (4.5H, s), 1.60-1.79 (2H, m), 2.79-2.98 (3H, m), 3.10-3.32 (3H, m),3.72-3.81 (1H, m), 4.70-5.02 (3H, m), 5.87-5.95 (2H, m), 6.16-6.21 (1H,m), 6.40-7.45 (14H, m), 7.87 (0.5H, s), 7.95 (0.5H, s)

ESI-MS (m/z): 707 [M+H]

Example 25-38)

[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-Trp(CHO)-NHSO₂CH₃(245 mg)

NMR (CDCl₃, δ): 0.73-0.90 (3H, m), 1.09-1.49 (6H, m), 3.03-3.45 (3H, m),3.11, 3.38 (3H, s), 4.00-4.19 (1H, m), 4.62-4.92 (1H, m), 5.91-5.99 (2H,m), 6.28 (1H, d, J=8 Hz), 6.52-6.79 (3H, m), 6.82-7.50 (5H, m),8.23-8.27 (1H, s)

ESI-MS: 530 [M+H]

The compounds of Examples 26-1) to 3), 14) to 16), 22) to 24), and 26)to 34) were obtained in substantially the same manner as that of Example7-1). And the compounds of Examples 26-4) to 13), and 17) to 21) wereobtained in substantially the same manner as that of 14-1).

Example 26-1)

N^(α)-[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-acetoxyheptanoyl]-L-tryptophan

NMR (CDCl₃, δ): 0.73-0.83 (3H, m), 1.03-1.50 (6H, m), 1.81 (1.5H, s),1.90 (1.5H, s), 3.08-3.48 (3H, m), 4.73-4.90 (1H, m), 5.40-5.53 (1H, m),5.83-5.96 (2H, m), 6.22-7.33 (10H, m), 8.33-8.46 (1H, m)

ESI-MS (m/z): 495 [M+H]

Example 26-2)

[(2R,3R)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyoctanoyl]-L-1-Nal-OH (148mg) [a less polar isomer, obtained by using preparative thin layerchromatography (CHCl₃:MeOH:AcOH=20:1:1)]

mp: 183-184° C.

Rf: 0.71 (CHCl₃:MeOH:AcOH=16:1:1)

NMR (DMSO-d₆, δ): 0.80 (3H, t, J=7 Hz), 0.94-1.42 (8H, m), 3.20-3.52(4H, m), 3.79-3.92 (1H, m), 4.50-4.60 (1H, m), 5.98 (2H, s), 6.72 (1H,d, J=8 Hz), 6.82 (1H, d, J=8 Hz), 6.87 (1H, s), 7.32-7.42 (2H, m),7.50-7.63 (2H, m), 7.81 (1H, d, J=8 Hz), 7.94 (1H, d, J=8 Hz), 8.18 (1H,d, J=8 Hz), 8.39 (1H, d, J=8 Hz)

ESI-MS: 478 [M+H]

Example 26-3)

N^(α)-[3-(1-t-Butoxycarbonyl-2-pentylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-tryptophanP NMR (CDCl₃, δ): 0.84-0.92 (3H, m), 1.18-1.38 (4H, m), 1.40-1.67 (11H,m), 2.75-3.43 (6H, m), 3.98-4.08 (1H, m), 4.73-4.97 (1H, m), 5.87-5.97(2H, m), 6.53-7.58 (9H, m), 7.63-7.90 (1H, m)

ESI-MS (m/z): 617 [M+H]

Example 26-4)

N^(α)-[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyheptanoyl]-3-(benzo[b]thiophen-3-yl)-L-alanine

NMR (DMSO-d₆, δ): 0.77 (3H, t, J=6 Hz), 0.97-1.40 (6H, m), 3.00-3.48(5H, m), 3.87-3.98 (1H, m), 4.49-4.65 (1H, m), 5.98 (2H, s), 6.68-7.48(6H, m), 7.70-8.00 (2H, m), 8.35 (1H, t, J=7 Hz)

ESI-MS (m/z): 470 [M+H]

Example 26-5

N^(α)-[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyheptanoyl]-3-(benzo[b]thiophen-1,1-dioxide-3-yl)-L-alanine

NMR (DMSO-d₆, δ): 0.63-0.95 (3H, m), 0.97-1.50 (6H, m), 2.93-3.70 (4H,m), 3.82-4.07 (1H, m), 4.10-4.36 (1H, m), 4.93-5.12 (1H, m), 5.82-6.17(2H, m), 6.50-8.10 (8H, m), 8.45-8.70 (1H, m)

ESI-MS (m/z): 502 [M+H]

Example 26-6)

[(2R,3R)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-Trp(Me)-OH

NMR (CDCl₃, δ): 0.80 (3H, t, J=7 Hz), 1.10-1.50 (6H, m), 3.20 (1H, d,J=8 Hz), 3.25-3.32 (2H, m), 3.69 (3H, s), 3.98-4.08 (1H, m), 4.72-4.82(1H, m), 5.90 (1H, s), 5.91 (1H, s), 6.16 (1H, d, J=7 Hz), 6.48 (1H, d,J=8 Hz), 6.57-6.63 (2H, m), 6.76 (1H, s), 7.07 (1H, t, J=7 Hz),7.18-7.28 (2H, m), 7.48 (1H, d, J=7 Hz)

ESI-MS (m/z): 467 [M+H]

Example 26-7

[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-Trp(Et)-OH

NMR (CDCl₃, δ): 0.79 (1.5H, t, J=7 Hz), 0.80 (1.5H, t, J=7 Hz),1.05-1.47 (9H, m), 3.15-3.30 (3H, m), 3.97-4.10 (3H, m), 4.73-4.89 (1H,m), 5.89-5.97 (2H, m), 6.17 (0.5H, d, J=7 Hz), 6.30 (0.5H, d, J=7 Hz),6.45-6.83 (4H, m), 6.97-7.50 (4H, m)

ESI-MS (m/z): 481 [M+H]

Example 26-8)

[(2R,3R)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-Trp(^(i)Pr)-OH

NMR (CDCl₃, δ): 0.81 (3H, t, J=7 Hz), 1.08-1.45 (6H, m), 1.45 (3H, d,J=7 Hz), 1.48 (3H, d, J=7 Hz), 3.18 (1H, d, J=7 Hz), 3.20-3.37 (2H, m),3.98-4.05 (1H, m), 4.58 (0.5H, q, J=7 Hz), 4.60 (0.5H, q, J=7 Hz),4.77-4.82 (1H, m), 5.90 (2H, s), 6.13 (1H, d, J=7 Hz), 6.46 (1H, d, J=7Hz), 6.56 (1H, s), 6.60 (1H, d, J=6 Hz), 6.98 (1H, s), 7.06 (1H, t, J=7Hz), 7.18 (1H, t, J=7 Hz), 7.32 (1H, d, J=7 Hz), 7.48 (1H, d, J=8 Hz)

ESI-MS (m/z): 495 [M+H]

Example 26-9)

[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyheptanoyl]-DL-Trp(5-Me)-OH

NMR (CDCl₃, δ): 0.74-0.83 (3H, m), 1.07-1.48 (6H, m), 2.40 (1.5H, s),2.45 (1.5H, s), 3.15-3.37 (3H, m), 4.00-4.10 (1H, m), 4.75-4.88 (1H, m),5.85-5.92 (2H, m), 6.29-6.83 (5H, m), 7.00-7.03 (1H, m), 7.18-7.31 (2H,m), 8.08-8.19 (1H, s)

ESI-MS (m/z): 467 [M+H]

Example 26-10)

[(2R,3R)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyheptanoyl]-DL-Trp(4-Me)-OH

NMR (CDCl₃, δ): 0.74-0.82 (3H, m), 1.08-1.48 (6H, m), 2.60 (3H, s),3.15-3.33 (2H, m), 3.50-3.60 (1H, m), 3.94-4.07 (1H, m), 4.68-4.80 (1H,m), 5.86-5.92 (2H, m), 6.25-6.38 (1H, m), 6.45-6.53 (1H, m), 6.55-6.63(2H, m), 6.79-6.82 (2H, m), 7.05 (1H, t, J=7 Hz), 7.17 (1H, d, J=7 Hz),8.22 (1H, s)

ESI-MS (m/z): 467 [M+H]

Example 26-11)

[(2R,3R)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyheptanoyl]-DL-Trp(6-Me)-OH

NMR (CDCl₃, δ): 0.78-0.87 (3H, m), 1.03-1.48 (6H, m), 2.42 (3H, s),3.17-3.33 (3H, m), 3.98-4.07 (1H, m), 4.77-4.83 (1H, m), 5.88 (1H, s),5.90 (1H, s), 6.23 (1H, d, J=7 Hz), 6.48 (1H, d, J=7 Hz), 6.59-6.82 (3H,m), 6.91 (1H, d, J=7 Hz), 7.10 (1H, s), 7.38 (1H, d, J=7 Hz), 8.03 (1H,s)

ESI-MS (m/z): 467 [M+H]

Example 26-12)

[(2R,3R)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyheptanoyl]-DL-Trp(7-Me)-OH

NMR (CDCl₃+CD₃OD, δ): 0.80-0.85 (3H, m), 1.10-1.50 (6H, m), 2.47 (3H,s), 3.18-3.43 (3H, m), 3.98-4.08 (1H, m), 4.73-4.83 (1H, m), 5.90-5.93(2H, m), 6.52-6.67 (4H, m), 6.93-7.05 (3H, m), 7.25-7.40 (2H, m)

ESI-MS (m/z): 467 [M+H]

Example 26-13)

N^(α)-[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyheptanoyl]-DL-7-azatryptophan

NMR (DMSO-d₆, δ): 0.76 (3H, t, J=6 Hz), 0.97-1.40 (6H, m), 2.95-3.15(2H, m), 3.46-3.50 (1H, m), 3.90-3.97 (1H, m), 4.45-4.55 (1H, m),5.96-5.99 (2H, m), 6.70-7.32 (6H, m), 7.70 (0.5H, d, J=7 Hz), 7.93(0.5H, d, J=7 Hz), 8.10-8.17 (2H, m)

ESI-MS (m/z): 454 [M+H]

Example 26-14)

[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-Trp(CHO)-OH(152 mg)

NMR (CDCl₃, δ): 0.79, 0.80 (3H, t, J=7 Hz), 1.05-1.48 (6H, m), 3.02-3.38(4H, m), 4.02-4.16 (1H, m), 4.71-4.95 (1H, m), 5.89-5.98 (2H, s),6.52-6.85 (5H, m), 7.00-7.62 (4H, m), 8.22-8.95 (1H, m)

ESI-MS: 481 [M+H]

Example 26-15)

[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-Trp(COOMe)-OH(206 mg)

NMR (CDCl₃, δ): 0.72-0.85 (3H, m), 1.08-1.50 (6H, m), 3.00-3.24 (3H, m),3.97, 3.99 (3H, s), 4.02-4.13 (1H, m), 4.73-4.96 (1H, m), 5.88, 5.93(2H, s), 6.34-6.66 (4H, m), 7.10-7.51 (14H, m), 8.02-8.18 (1H, m)

ESI-MS: 511 [M+H]

Example 26-16)

[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-Trp(CH₂CO₂Et)-OH

NMR (CDCl₃, δ): 0.78 (1.5H, t, J=7 Hz), 0.81 (1.5H, t, J=7 Hz),1.07-1.47 (11H, m), 3.19-3.42 (3H, m), 3.90-4.09 (1H, m), 4.12 (1H, q,J=7 Hz), 4.20 (1H, q, J=7 Hz), 4.68 (1H, s), 4.76 (1H, s), 4.77-4.91(1H, m), 5.88-5.97 (2H, m), 6.40-6.85 (5H, m), 7.00-7.22 (3H, m), 7.40(0.5H, d, J=7 Hz), 7.52 (0.5H, d, J=7 Hz)

ESI-MS (m/z): 539 [M+H]

Example 26-17)

[(2R,3R)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-Trp(CH₂CONMe₂)-OH

NMR (CDCl₃, δ): 0.79 (3H, t, J=6 Hz), 1.08-1.63 (6H, m), 2.93 (3H, s),2.98 (3H, s), 3.22-3.37 (3H, m), 3.86-3.92 (1H, m), 4.48-4.72 (2H, m),4.77-4.83 (1H, m), 5.87 (2H, s), 6.47-6.57 (2H, m), 6.68 (1H, s), 6.93(1H, s), 7.06-7.22 (4H, m), 7.55 (1H, d, J=7 Hz)

ESI-MS (m/z): 538 [M+H]

Example 26-18)

N^(α)-[3-Hydroxy-3,3-di(2-pyridyl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-tryptophan

NMR (CDCl₃, δ): 3.13-3.20 (2H, m), 4.58-4.75 (1H, m), 5.26, 5.47 (total1H, s), 5.77-5.87 (2H, m), 6.29-6.72 (4H, m), 6.84-7.69 (10H, m),8.12-8.39 (4H, m)

ESI-MS: 551 [M+H]

Example 26-19)

N^(α)-[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-cyclopropyl-3-hydroxypropionyl]-L-tryptophan

NMR (CDCl₃, δ): −0.10-0.40 (4H, m), 0.52-0.78 (1H, m), 3.10-3.50 (5H,m), 4.70-4.93 (1H, m), 5.83-5.94 (1H, m), 6.50-6.72 (4H, m), 6.87-7.50(4H, m), 8.26 (0.5H, s), 8.35 (0.5H, s)

ESI-MS (m/z) 437 [M+H]

Example 26-20)

N^(α)-[(2RS,3SR)-3-Hydroxy-3-(2-biphenylyl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-tryptophan

NMR (CDCl₃, δ): 3.16-3.26 (2H, m), 3.45-3.53 (2H, m), 4.78-4.86 (1H, m),5.24 (0.5H, d, J=8 Hz), 5.32 (0.5H, d, J=9 Hz), 5.82 (1H, d, J=7 Hz),5.88 (1H, d, J=5 Hz), 5.97-6.11 (3H, m), 6.36-6.44 (0.5H, m), 6.66(0.5H, dd, J=3, 13 Hz), 6.94-7.47 (14H, m), 7.96-8.07 (1H, m)

ESI-MS: 549 [M+H]

Example 26-21)

[(2R,3R)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyoctanoyl]-L-Trp-OH (118mg)

NMR (CDCl₃, δ): 0.82 (3H, t, J=7 Hz), 1.01-1.52 (8H, m), 3.10-3.38 (3H,m), 3.94-4.10 (1H, m), 4.73-4.88 (1H, m), 5.87 (2H, d, J=5 Hz), 6.32(1H, d, J=9 Hz), 6.48 (1H, d, J=7 Hz), 6.58 (1H, d, J=8 Hz), 6.74 (1H,d, J=3 Hz), 7.08 (1H, t, J=7 Hz), 7.18 (1H, t, J=7 Hz), 7.29 (1H, d, J=7Hz), 7.48 (1H, d, J=7 Hz), 8.26 (1H, s)

ESI-MS: 467 [M+H]

Example 26-22)

N^(α)-[3-(1-tert-Butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-tryptophan

Rf: 0.13 (benzene:ethyl acetate:acetic acid=20:20:1)

ESI-MS: 603 (M+H)

Example 26-23)

[3-(1-t-Butoxycarbonyl-2-pentylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-Trp(CH₂CO₂^(t)Bu)-OH p NMR (CDCl₃, δ): 0.83-0.90 (3H, m), 1.16-1.34 (4H, m), 1.37(4.5H, s), 1.40 (4.5H, s), 1.47-1.63 (11H, m), 2.78-3.02 (2H, m),3.05-3.38 (3H, m), 3.82-3.98 (1H, m), 4.40-4.50 (2H, m), 4.68-4.87 (1H,m), 5.85-5.98 (2H, m), 6.37-7.60 (10H, m)

ESI-MS (m/z): 731 [M+H]

Example 26-24)

N-[(2S)-3-(1-tert-Butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-3-(1-naphthyl)alanine

NMR (CDCl₃, δ): 0.79 (3H, t, J=8 Hz), 1.09-1.19 (2H, m), 1.33-1.46 (2H,m), 1.55 (9H, s), 2.70-2.92 (3H, m), 3.06-3.13 (1H, m), 3.34-3.42 (1H,m), 3.62-3.71 (1H, m), 4.01-4.08 (1H, m), 4.77-4.85 (1H, m), 5.90 (2H,d, J=2 Hz), 6.58-6.63 (2H, m), 6.70 (1H, s), 6.90 (1H, s), 7.19-7.23(2H, m), 7.40-7.50 (2H, m), 7.66-7.80 (3H, m), 8.33 (1H, d, J=8 Hz)

ESI-MS: 614 [M+H]

Example 26-25)

A mixture of[3-(1-tert-butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-Trp(CH₂CO₂Et)-OBzl(300 mg) and 10% palladium on activated carbon (300 mg) in ethanol (20ml) and water (2 ml) was shaken under hydrogen atmosphere (3 atmosphericpressure) at ambient temperature for 1 hour. The mixture was filteredthrough a bed of celite and the filtrate was evaporated in vacuo. Theresidue was diluted with ethyl acetate and the solution was dried overmagnesium sulfate. Filtering and removal of the solvents afforded acrude product. The crude diastereomers were separated by preparative TLC(benzene:ethyl acetate:acetic acid=20:20:1) to give[(2S)-3-(1-tert-butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-Trp(CH₂CO₂Et)-OH(70 mg) as a slightly yellow powder.

NMR (CDCl₃, δ): 0.87 (3H, t, J=7 Hz), 1.22 (3H, t, J=8 Hz), 1.23-1.32(2H, m), 1.58-1.67 (2H, m), 1.57 (9H, s), 2.82-2.93 (3H, m), 3.02-3.18(2H, m), 3.27-3.35 (1H, m), 3.90 (1H, t, J=8 Hz), 4.14 (2H, q, J=8 Hz),4.68 (2H, s), 4.69-4.77 (1H, m), 5.90 (2H, d, J=2 Hz), 6.63 (2H, s),6.77 (1H, s), 6.81 (1H, s), 6.84 (1H, s), 6.99-7.16 (4H, m), 7.58 (1H,d, J=8 Hz)

ESI-MS: 689 [M+H]

The following compounds were obtained in substantially the same manneras that of Example 26-25).

Example 26-26

[(2S)-3-(1-tert-Butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-Trp(CH₂CH₂CO₂Et)-OHas a white solid

NMR (CDCl₃, δ): 0.86 (3H, t, J=8 Hz), 1.19 (3H, t, J=8 Hz), 1.21-1.30(2H, m), 1.45-1.56 (2H, m), 1.54 (9H, s), 2.63-2.71 (2H, m), 2.80-2.93(3H, m), 3.06-3.16 (2H, m), 3.23-3.32 (1H, m), 3.90-3.97 (1H, m), 4.08(2H, q, J=8 Hz), 4.24-4.29 (2H, m), 4.67-4.75 (1H, m), 5.89-5.95 (2H,m), 6.62 (2H, s), 6.79 (1H, s), 6.83-6.87 (2H, m), 6.97-7.25 (4H, m),7.57 (1H, d, J=8 Hz)

ESI-MS: 703 [M+H]

Example 26-27

[(2S)-3-(1-tert-Butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-Trp(Me)-OH

NMR (CDCl₃, δ): 0.84 (3H, t, J=8 Hz), 1.20-1.31 (2H, m), 1.42-1.55 (2H,m), 1.56 (9H, s), 2.80-2.92 (3H, m), 3.00-3.18 (2H, m), 3.26-3.34 (1H,m), 3.60 (3H, s), 3.95-4.02 (1H, m), 4.68-4.74 (1H, m), 5.99, 6.01(total 2H, s), 6.63 (2H, s), 6.73 (1H, s), 6.77 (1H, s), 6.87 (1H, s),6.98 (1H, t, J=8 Hz), 7.09-7.26 (3H, m), 7.55 (1H, d, J=8 Hz)

ESI-MS: 617 [M+H]

Example 26-28)

[(2RS)-3-(1-tert-Butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-Trp(CH₂CO₂^(t)Bu)-OH (2R:2S=1:4)

Rf: 0.28 (10% methanol in chloroform)

ESI-MS: 575 [M+H]

Example 26-29)

[(2S)-3-(1-tert-Butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-Trp(Et)-OH

NMR (CDCl₃, δ): 0.84 (3H, t, J=8 Hz), 1.19-1.29 (2H, m), 1.35 (3H, t,J=8 Hz), 1.44-1.55 (2H, m), 1.56 (9H, s), 2.76-2.93 (3H, m), 3.03-3.17(2H, m), 3.26-3.34 (1H, m), 3.95-4.06 (3H, m), 4.68-4.76 (1H, m),5.89-6.03 (2H, m), 6.62 (2H, s), 6.77 (1H, s), 6.82 (1H, s), 6.86 (1H,s), 7.00 (1H, t, J=8 Hz), 7.13 (1H, t, J=8 Hz), 7.20-7.27 (2H, m), 7.57(1H, d, J=8 Hz)

ESI-MS: 631 [M+H]

Example 26-30

N^(α)-[3-(1H-Imidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-tryptophanHydrochloride

NMR (DMSO-d₆, δ): 2.83-3.13 (4H, m),3.88-3.97 (1H, m), 4.37-4.46 (1H,m), 5.98 (2H, s), 6.70-7.45 (11H, m), 8.37 (1H, d, J=8 Hz), 8.58-8.65(1H, m)

ESI-MS: 447 [M+H]

Example 26-31)

N^(α)-[3-(1-Methylimidazol-5-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-tryptophan

NMR (DMSO-d₆, δ): 2.72-2.98 (4H, m), 3.09-3.18 (1H, m), 3.43, 3.47(total 3H, s), 3.80-3.90 (1H, br), 4.30-4.39 (1H, br), 5.94, 5.96 (total2H, s), 6.47-6.50 (1H, br s), 6.74-7.05 (6H, m), 7.28-7.53 (3H, m),7.93-8.00 (1H, br)

ESI-MS: 461 [M+H]

Example 26-32

[3-(1-t-Butoxycarbonyl-2-ethylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-tryptophan

NMR (DMSO-d₆, δ): 1.11-1.19 (3H, m), 1.45 (4.5H, s), 1.52 (4.5H, s),2.62-2.73 (1H, m), 2.80-2.89 (2H, m), 2.94-3.10 (3H, m), 3.90-3.97 (1H,m), 4.37-4.46 (1H, m), 5.95 (2H, s), 6.70-6.78 (2H, m), 6.82-7.07 (5H,m), 7.32 (1H, d, J=7 Hz), 7.47 (1H, d, J=6 Hz), 8.21-8.29 (1H, m)

ESI-MS (m/z): 575 [M+H]

Example 26-33)

N^(α)-[(2RS)-3-(1-tert-Butoxycarbonyl-2-n-propylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-tryptophan(2R:2S=1:4)

Rf: 0.10 (10% methanol in chloroform)

ESI-MS 589 [M+H]

The following compounds were obtained in substantially the same manneras that of Example 28-3).

Example 27-1)

N(-[3-(2-n-Butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-tryptophanEthyl Ester Hydrochloride

NMR (DMSO-d₆, δ): 0.81-0.90 (3H, m), 0.95-1.11 (3H, m), 1.16-1.27 (2H,m), 1.56-1.68 (2H, m), 2.77-2.90 (3H, m), 2.98-3.18 (4H, m), 3.86-3.98(3H, m), 4.36-4.49 (1H, m), 5.98 (2H, s), 6.73 (1H, t, J=8 Hz), 6.80(1H, t, J=8 Hz), 6.86-7.12 (5H, m), 7.29-7.45 (2H, m), 8.52-8.59 (1H, m)

ESI-MS: 531 [M+H]

Example 27-2)

N-[(2S)-3-(2-n-Butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-3-(1-naphthyl)alaninetrifluoroacetic Acid Salt

NMR (DMSO-d₆, δ): 0.83 (3H, t, J=8 Hz), 1.13-1.23 (2H, m), 1.51-1.61(2H, m), 2.77 (2H, t, J=8 Hz), 2.78-2.87 (1H, m), 2.99-3.10 (1H, m),3.17-3.25 (1H, m), 3.50-3.80 (3H, m), 4.45-4.53 (1H, m), 6.00 (2H, s),6.72 (1H, d, J=8 Hz), 6.82 (1H, d, J=8 Hz), 6.86 (1H, s), 7.01 (1H, s),7.19 (1H, d, J=8 Hz), 7.32 (1H, t, J=8 Hz), 7.50-7.60 (2H, m), 7.79 (1H,d, J=8 Hz), 7.92 (1H, d, J=8 Hz), 8.08 (1H, d, J=8 Hz), 8.52 (1H, d, J=8Hz)

ESI-MS: 514 [M+H]

Example 27-3)

[(2S)-3-(2-n-Butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-Trp(Me)-OHtrifluoroacetic Acid Salt

NMR (DMSO-d₆, δ): 0.83 (3H, t, J=8 Hz), 1.13-1.25 (2H, m), 1.53-1.63(2H, m), 2.77 (2H, t, J=8 Hz), 2.86-3.18 (4H, m), 3.67 (3H, m),3.75-3.88 (2H, m), 4.41 (1H, dd, J=8, 14 Hz), 5.98 (2H, s), 6.74 (1H, d,J=8 Hz), 6.83 (1H, d, J=8 Hz), 6.89 (2H, d, J=5 Hz), 7.00 (1H, t, J=8Hz), 7.08-7.16 (2H, m), 7.36 (1H, d, J=8 Hz), 7.48 (1H, d, J=8 Hz), 8.37(1H, d, J=8 Hz)

ESI-MS: 517 [M+H]

Example 27-4)

[(2RS)-3-(2-n-Butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-Trp(CH₂CO₂Me)-OMehydrochloride (2R:2S=1:4)

NMR (DMSO-d₆, δ): 0.80-0.89 (3H, m), 1.17-1.25 (2H, m), 1.58-1.67 (2H,m), 2.76-3.15 (7H, m), 3.49 (3H, s), 3.64 (3H, s), 3.85-3.93 (1H, m),4.39-4.48 (1H, m), 5.03-5.06 (2H, br s), 5.96-5.99 (2H, br s), 6.70-6.88(3H, m), 6.98-7.14 (4H, m), 7.29-7.36 (1H, m), 7.43-7.48 (1H, m),8.53-8.58 (1H, m)

ESI-MS: 589 [M+H]

Example 27-5)

N^(α)-[(2S)-3-(2-n-Butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-Trp(Et)-OHtrifluoroacetic Acid Salt

NMR (DMSO-d₆, δ): 0.82 (3H, t, J=8 Hz), 1.12-1.23 (2H, m), 1.28 (3H, t,J=8 Hz), 1.52-1.62 (2H, m), 2.77 (2H, t, J=8 Hz), 2.85-3.15 (4H, m),3.80-3.88 (1H, m), 4.05-4.13 (2H, m), 4.36-4.45 (1H, m), 5.98 (2H, s),6.73 (1H, d, J=8 Hz), 6.82 (1H, d, J=8 Hz), 6.90 (1H, s), 6.96-7.02 (2H,m), 7.08-7.15 (2H, m), 7.39 (1H, d, J=8 Hz), 7.48 (1H, d, J=8 Hz), 8.37(1H, d, J=8 Hz)

ESI-MS: 531 [M+H]

Example 27-6)

A mixture ofN^(α)-[3-(1-triphenylmethylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-tryptophanbenzyl ester (290 mg) in 80% acetic acid-water (5 ml) was stirred at 50°C. for 5 hours. The resulting mixture was cooled to ambient temperatureand the solution was diluted with water. Carbinol was removed byfiltration and the filtrate was neutralized with saturated sodiumhydroxide aqueous solution, and then the aqueous layer was extractedwith ethyl acetate. Drying, filtering and removal of the solventsaffordedN^(α)-[3-(imidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-tryptophanbenzyl ester (180 mg) as a yellow powder.

NMR (CDCl₃, δ): 2.77-2.88 (1H, m), 3.18-3.32 (2H, m), 3.86-3.97 (1H, m),4.75-4.86 (1H, m), 4.98-5.06 (2H, m), 5.83-5.89 (2H, m), 6.57-6.77 (5H,m), 6.98 (1H, t, J=8 Hz), 7.08-7.40 (10H, m), 7.88-7.95 (1H, m),8.67-8.70 (1H, br)

ESI-MS: 537 [M+H]

Example 27-7)

N^(α)-[(2S)-3-(2-Ethylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-tryptophantrifluoroacetic acid salt was obtained according to a similar manner tothat of Example 28-3).

NMR (DMSO-d₆, δ): 1.18 (3H, t, J=6 Hz), 2.68-3.17 (6H, m), 3.82-3.88(1H, m), 4.41-4.49 (1H, m), 5.98 (2H, s), 6.73-7.08 (8H, m), 7.32 (1H,d, J=7 Hz), 7.44 (1H, d, J=7 Hz), 8.35 (1H, d, J=7 Hz)

ESI-MS (m/z): 475 [M+H]

Example 27-8)

N-[(2S)-3-(2-n-Propylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-tryptophantrifluoroacetic acid salt was obtained according to a similar manner tothat of Preparation 36-21).

NMR (DMSO-d₆, δ): 0.79 (3H, t, J=8 Hz), 1.63 (2H, q, J=8 Hz), 2.76 (2H,t, J=8 Hz), 2.82-3.25 (6H, m), 3.85 (1H, t, J=8 Hz), 4.45 (1H, dd, J=7,15 Hz), 5.98 (2H, s), 6.75 (1H, d, J=9 Hz), 6.82 (1H, d, J=9 Hz), 6.89(1H, s), 6.93-6.99 (2H, m), 7.02-7.08 (2H, m), 7.33 (1H, d, J=8 Hz),7.47 (1H, d, J=8 Hz), 8.39 (1H, d, J=8 Hz)

ESI-MS: 489.1 [M+H]

Example 27-9)

N^(α)-[(2S)-3-(2-Pentylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-tryptophantrifluoroacetic acid salt was obtained according to a similar manner tothat of Example 28-3).

NMR (DMSO-d₆, δ): 0.81 (3H, t, J=7 Hz), 1.07-1.30 (4H, m), 1.52-1.66(2H, m), 2.70-3.13 (6H, m), 3.83-3.88 (1H, m), 4.40-4.50 (1H, m), 5.97(2H, s), 6.72-7.07 (8H, m), 7.33 (1H, d, J=8 Hz), 7.47 (1H, d, J=7 Hz),8.38 (1H, d, J=7 Hz)

ESI-MS (m/z): 517 [M+H]

Example 27-10)

N^(α)-[(2S)-3-(2-n-Butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-tryptophanhydrochloride was obtained according to a similar manner to that ofExample 28-1) fromN^(α)-[(2S)-3-(1-tert-butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-tryptophanethyl ester.

NMR (DMSO-d₆, δ): 0.83 (3H, t, J=8 Hz), 1.16-1.24 (2H, m), 1.56-1.67(2H, m), 2.78 (2H, t, J=8 Hz), 2.82-2.99 (2H, m), 3.06-3.15 (2H, m),3.30-3.40 (1H, m),3.93 (1H, dd, J=8, 10 Hz), 4.45 (1H, dd, J=8, 14 Hz),5.98 (2H, s), 6.76 (1H, d, J=8 Hz), 6.81 (1H, d, J=8 Hz), 6.90 (1H, s),6.95-7.08 (4H, m), 7.34 (1H, d, J=8 Hz), 7.47 (1H, d, J=8 Hz), 8.43 (1H,d, J=8 Hz)

ESI-MS: 503 [M+H]

Example 28-1)

A mixture of[(2S)-3-(1-tert-butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-Trp(CH₂CO₂Et)-OH(60 mg) in ethanol (4 ml) and 1N sodium hydroxide aqueous solution (2ml) was stirred at ambient temperature for 1 hour. The reaction wasquenched with 1N hydrochloric acid (2 ml), and then the resultingmixture was diluted with ethyl acetate followed by washing with water.Drying, filtering and removal of the solvents afforded[(2S)-3-(2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-Trp(CH₂CO₂H)-OH(40 mg) as a slightly yellow powder.

NMR (DMSO-d₆, δ): 0.83 (3H, t, J=8 Hz), 1.13-1.25 (2H, m), 1.50-1.63(2H, m), 2.73 (2H, t, J=8 Hz), 2.80-3.17 (5H, m), 3.87 (1H, t, J=8 Hz),4.38-4.48 (1H, m), 4.87 (2H, s), 5.97 (2H, s), 6.73 (1H, d, J=8 Hz),6.81 (1H, d, J=8 Hz), 6.86-6.92 (2H, m), 6.97-7.13 (3H, m), 7.32 (1H, d,J=8 Hz), 7.49 (1H, d, J=8 Hz), 8.36 (1H, d, J=8 Hz)

ESI-MS: 561 [M+H]

The following compound was obtained in substantially the same manner asthat of Example 28-1).

Example 28-2)

[(2S)-3-(2-n-Butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-Trp(CH₂CH₂CO₂H)-OH

NMR (DMSO-d₆, δ): 0.80-0.88 (3H, m), 1.10-1.25 (2H, m), 1.56-1.65 (2H,m), 2.66-3.12 (8H, m), 3.84-3.92 (1H, m), 4.26-4.43 (3H, m), 5.97 (2H,s), 6.71-7.02 (6H, m), 7.08-7.15 (1H, m), 7.38-7.49 (2H, m), 8.30-8.36(1H, m)

ESI-MS: 575 [M+H]

Example 28-3)

A solution of[(2RS)-3-(1-tert-butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-Trp(CH₂CO₂^(t)Bu)-OMe (190 mg) in trifluoroacetic acid (5 ml) was stirred atambient temperature for 30 minutes. Trifluoroacetic acid was evaporatedin vacuo and the residue was triturated with ether-n-hexane (1:3) togive[(2RS)-3-(2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-Trp(CH₂CO₂H)-OMetrifluoroacetic acid salt (2R:2S=1:4) (173 mg) as a slightly yellowpowder.

NMR (DMSO-d₆, δ): 0.80-0.89 (3H, m), 1.17-1.30 (2H, m), 1.57-1.67 (2H,m), 2.75-3.18 (9H, m), 3.48, 3.55 (total 3H, s), 3.79-3.86 (1H, m),4.40-4.48 (1H, m), 4.80, 4.90 (total 2H, s), 5.98 (2H, s), 6.70-6.86(3H, m), 6.95-7.13 (3H, m), 7.28-7.38 (1H, m), 7.45 (1H, d, J=8 Hz),8.52-8.58 (1H, m)

ESI-MS: 575 [M+H]

Example 28-4)

A solution of[(2RS)-3-(1-t-butoxycarbonyl-2-pentylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-Trp(CH₂CO₂^(t)Bu)-OH (160 mg) in trifluoroacetic acid (20 ml) was stirred atambient temperature for 30 minutes. The solution was concentrated invacuo and the diastereomers were separated by preparative thin-layerchromatography (chloroform:methanol:acetic acid=8:1:1) to give[(2S)-3-(2-pentylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-Trp(CH₂CO₂H)-OHacetic acid salt (70 mg) as an amorphous powder.

NMR (DMSO-d₆, δ): 0.87-0.90 (3H, m), 1.13-1.35 (4H, m), 1.43-1.70 (2H,m), 2.60-2.78 (2H, m), 2.95-3.22 (5H, m), 3.35-3.45 (1H, m), 4.05-4.18(2H, m), 4.52-4.68 (1H, m), 5.93 (2H, s), 6.30-6.45 (1H, m), 6.65-6.75(3H, m), 6.85-6.95 (3H, m), 7.02-7.10 (1H, m), 7.20-7.30 (1H, m),7.35-7.44 (1H, m)

ESI-MS (m/z): 575 [M+H]

The following compounds were obtained in substantially the same manneras that of Example 14-1).

Example 29-1)

[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-Trp(CH₂CO₂H)-OHfrom[(2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-Trp(CH₂CO₂Et)-OBzl

Rf: 0.30, 0.40 (chloroform:methanol:acetic acid=8:1:1)

ESI-MS (m/z): 509 [M-H]

Example 29-2)

[(2R,3R)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-Trp(CH₂CO₂H)-OHfrom[(2R,3R)-2-(3,4-methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-Trp(CH₂CO₂Me)-OMe

NMR (DMSO-d₆, δ): 0.78 (3H, t, J=7 Hz), 1.00-1.40 (6H, m), 2.95-3.20(3H, m), 3.42 (1H, d, J=8 Hz), 3.88-3.98 (1H, m), 4.48-4.56 (1H, m),4.92 (2H, s), 5.96 (1H, s), 5.97 (1H, s), 6.72-6.83 (2H, m), 6.90 (1H,s), 7.00-7.15 (2H, m), 7.18 (1H, s), 7.31 (1H, d, J=7 Hz), 7.56 (1H, d,J=7 Hz), 8.23 (1H, d, J=7 Hz)

ESI-MS (m/z): 511 [M+H]

Example 29-3)

[(2R,3R)-3-Hydroxy-2-(3,4-methylenedioxyphenyl)-heptanoyl]-L-Trp(CH₂CH₂CO₂H)-OHfrom[(2R,3R)-3-hydroxy-2-(3,4-methylenedioxyphenyl)heptanoyl]-L-Trp(CH₂CH₂CO₂Et)-OMe

NMR (DMSO-d₆, δ): 0.78 (3H, t, J=7 Hz), 1.05-1.34 (6H, m), 2.67-2.74(2H, m), 2.98-3.16 (2H, m), 3.39-3.46 (2H, m), 3.88-3.96 (1H, br), 4.32(2H, t, J=8 Hz), 4.49 (1H, dd, J=7, 14 Hz), 5.96 (2H, s), 6.74 (1H, d,J=7 Hz), 6.80 (1H, d, J=7 Hz), 6.88 (1H, s), 7.00 (1H, t, J=8 Hz), 7.12(1H, t, J=8 Hz), 7.19 (1H, s), 7.42 (1H, d, J=8 Hz), 7.52 (1H, d, J=8Hz), 8.17 (1H, d, J=8 Hz)

ESI-MS: 525 [M+H]

Example 29-4)

[(2R,3R)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyoctanoyl]-L-Trp(CH₂COOH)-OH(55 mg), as a less polar isomer from[(2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-hydroxyoctanoyl]-L-Trp(CH₂COOEt)-OBzlby using preparative thin layer chromatography (CHCl₃:MeOH:AcOH=16:1:1)mp: 116-118° C.

Rf: 0.40 (CHCl₃:MeOH:AcOH=8:1:1)

NMR (DMSO-d₆l δ): 0.80 (3H, t, J=7 Hz), 1.01-1.45 (8H, m), 2.98 (2H, m),3.23-3.38 (1H, m), 3.88-3.98 (1H, m), 4.45-4.57 (1H, m), 4.90 (2H, s),5.92-6.02 (2H, m), 6.75 (1H, d, J=8 Hz), 6.82 (1H, d, J=8 Hz), 7.02 (1H,t, J=8 Hz), 7.12 (1H, t, J=8 Hz), 7.18 (1H, s), 7.32 (1H, d, J=8 Hz),7.57 (1H, d, J=8 Hz), 8.23 (1H, d, J=8 Hz)

ESI-MS: 525 [M+H]

Example 29-5)

[(2RS)-3-(1-tert-Butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-Trp(CH₂CO₂H)-OH(2R:2S=1:4) was obtained as a white powder according to a similar mannerto that of Example 26-25) from[(2RS)-3-(1-tert-butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-Trp(CH₂CO₂Bzl)-OBzl.

NMR (CDCl₃, δ): 0.86-0.93 (3H, m), 1.22-1.33 (4H, m), 1.52, 1.57 (total9H, s), 2.80-3.05 (3H, m), 3.55-3.80 (2H, m), 4.60-4.72 (3H, m),5.80-5.85 (2H, br s), 6.44-6.52 (3H, m), 6.68-6.76 (3H, m), 6.88-7.22(4H, m), 7.50-7.56 (1H, m)

ESI-MS: 661 [M+H]

Example 30-1)

To a solution ofN^(α)-[(2R,3R)-2-(3,4-methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-tryptophan(300 mg) in N,N-dimethylformamide (10 ml) were added potassium carbonate(69 mg) and ethyl iodide (155 mg) and the mixture was stirred at ambienttemperature for 3 hours. The mixture was diluted with ethyl acetate (20ml) and the solution was washed with 0.5N hydrochloric acid (20 ml×2),saturated sodium bicarbonate aqueous solution (20 ml×2) and brine (20ml) successively and the organic layer was dried over magnesium sulfate.The solution was concentrated in vacuo and the residue was purified bysilica gel column chromatography (hexane:ethyl acetate=2:1) to give N[(2R,3R)-2-(3,4-methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-tryptophanethyl ester as an amorphous powder (260 mg).

NMR (CDCl₃, δ): 0.82 (3H, t, J=7 Hz), 1.18 (3H, t, J=7 Hz), 1.20-1.53(6H, m), 3.13-3.36 (3H, m), 3.97-4.16 (4H, m), 4.78-4.88 (1H, m), 5.90(2H, s), 6.10 (1H, d, J=8 Hz), 6.53 (1H, d, J=8 Hz), 6.58-6.68 (2H, m),6.87-6.93 (1H, m), 7.10 (1H, t, J=7 Hz), 7.18 (1H, t, J=7 Hz), 7.32 (1H,d, J=8 Hz), 7.48 (1H, d, J=8 Hz), 8.10 (1H, s)

ESI-MS (m/z): 481 [M+H]

Example 30-2)

To a solution of[(2RS)-3-(1-tert-butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl-L-Trp(CH₂CO₂^(t)Bu)-OH (190 mg) in benzene (7 ml) and methanol (2 ml) was addeddropwise trimethylsilyldiazomethane (0.2 ml, 2.0M n-hexane solution) andthe mixture was stirred at ambient temperature for 2 hours. The mixturewas evaporated in vacuo to give[(2RS)-3-(1-tert-butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-Trp(CH₂CO₂^(t)Bu)-OMe (2R:2S=1:4) (200 mg) as a slightly yellow amorphous powder.

NMR (CDCl₃, δ): 0.86-0.96 (3H, m), 1.26-1.69 (6H, m), 1.46, 1.57 (total9H, s), 1.52, 1.62 (total 9H, s), 2.80-2.96 (3H, m), 3.10-3.30 (3H, m),3.56, 3.60 (total 3H, s), 3.76-3.83 (1H, m), 4.55, 4.66 (total 2H, s),5.90 (2H, s), 6.18-6.30 (1H, m), 6.65-6.94 (4H, m), 7.04-7.19 (3H, m),7.30, 7.44 (total 1H, d, J=8 Hz)

ESI-MS: 731 [M+H]

Example 31-1)

To a solution of[(2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-Trp(CH₂CO₂H)-OH(1.15 g) in methanol (20 ml) was added dropwisetrimethylsilyldiazomethane (2 ml, 2.0M n-hexane solution) and themixture was stirred at ambient temperature for 30 minutes. The solutionwas concentrated in vacuo and the diastereomers were separated by silicagel column chromatography (hexane:ethyl acetate=2:1) to give[(2R,3R)-2-(3,4-methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-Trp(CH₂CO₂Me)-OMe(313 mg) as an amorphous powder.

NMR (CDCl₃, δ): 0.82 (3H, t, J=7 Hz), 1.12-1.50 (6H, m), 3.20-3.35 (3H,m), 3.65 (3H, s), 3.75 (3H, s), 3.96-3.98 (1H, m), 4.00-4.10 (1H, m),4.78 (2H, s), 4.81-4.89 (1H, m), 5.91 (1H, s), 5.92 (1H, s), 6.19 (1H,d, J=7 Hz), 6.55-6.68 (3H, m), 6.81 (1H, s), 7.09-7.26 (3H, m), 7.48(1H, d, J=6 Hz)

ESI-MS (m/z): 539 [M+H]

Example 31-2)

[(2RS)-3-(1-tert-Butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-Trp(CH₂CO₂Me)-OMe(2R:2S=1:4) was obtained as a white amorphous powder according to asimilar manner to that of Example 31-1).

Rf: 0.72 (10% methanol in chloroform)

NMR (CDCl₃, δ): 0.88-0.97 (3H, m), 1.32-1.42 (2H, m), 1.53, 1.62 (total9H, s), 1.58-1.69 (2H, m), 2.83-2.97 (3H, m), 3.10-3.30 (3H, m), 3.56,3.60 (total 3H, s), 3.73 (3H, s), 3.76-3.82 (1H, m), 4.78 (2H, s),4.79-4.86 (1H, m), 5.90 (2H, s), 6.18-6.27 (1H, m), 6.65-6.72 (3H, m),6.89-6.93 (2H, m), 7.08-7.20 (3H, m), 7.47 (1H, d, J=8 Hz)

ESI-MS 689 [M+H]

Example 32

To a solution ofN^(α)-[(2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-tryptophanbenzyl ester (255 mg) in dichloromethane (5 ml) were added pyridine (74mg), acetic anhydride (72 mg) and 4-(dimethylamino)pyridine (11 mg) at5° C. and the mixture was stirred at ambient temperature for 18 hours.The mixture was diluted with ethyl acetate (20 ml) and the solution waswashed with 0.5N hydrochloric acid (20 ml×2), saturated sodiumbicarbonate aqueous solution (20 ml×2) and brine (20 ml) successivelyand the organic layer was dried over magnesium sulfate. The solution wasfiltered and concentrated in vacuo to giveN^(α)-[(2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-acetoxyheptanoyl]-L-tryptophanbenzyl ester as an oil.

NMR (CDCl₃, δ): 0.73-0.85 (3H, m), 1.07-1.55 (6H, m), 1.92 (1.5H, s),1.96 (1.5H, s), 3.12-3.30 (2H, m), 3.38-3.54 (1H, m), 4.92-5.03 (2H, m),5.05-5.13 (1H, m), 5.43-5.52 (1H, m), 5.88-6.00 (2H, m), 6.10 (0.5H, d,J=8 Hz), 6.22 (0.5H, d, J=8 Hz), 6.43-6.88 (4H, m), 6.98-7.60 (9H, m),7.92 (0.5H, 3), 8.00 (0.5H, s)

ESI-MS (m/z): 585 [M+H]

Example 33

To a solution ofN-[(2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-hydroxyheptanoyl]-3-(benzo[b]thiophen-3-yl)-L-alaninemethyl ester (280 mg) in dichloromethane (5 ml) was addedm-chloroperbenzoic acid (250 mg) and the mixture was stirred at ambienttemperature for 2 hours. After the mixture was concentrated in vacuo,the residue was added to 10% sodium thiosulfate aqueous solution (20 ml)and ethyl acetate (20 ml). The organic layer was washed with saturatedsodium bicarbonate aqueous solution (20 ml×2) and brine (20 ml)successively and the organic layer was dried over magnesium sulfate. Thesolution was filtered and concentrated in vacuo to giveN^(α)-[(2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-hydroxyheptanoyl]-3-(benzo[b]thiophen-1,1-dioxide-3-yl)-L-alaninemethyl ester as an amorphous powder (323 mg).

NMR (CDCl₃, δ): 0.80 (3H, t, J=7 Hz), 1.10-1.50 (6H, m), 2.95-3.21 (2H,m), 3.22-3.33 (1H, m), 3.40-3.53 (1H, m), 5.92-5.98 (2H, m), 6.10 (0.5H,s), 6.54 (0.5H, s), 6.32 (0.5H, d, J=7 Hz), 6.39 (0.5H, d, J=7 Hz),6.66-6.80 (3H, m), 7.40-7.77 (4H, m)

ESI-MS (m/z): 516 [M+H]

Example 34

A solution of[(2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-Trp(CH₂CO₂Et)-OH(72 mg) in ammonia solution (5 ml, 7.5N methanol solution) was stirredat ambient temperature for 72 hours. The solution was concentrated invacuo to give[(2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-Trp(CH₂CONH₂)-OH(60 mg) as an amorphous powder.

NMR (DMSO-d₆, δ): 0.73-0.79 (3H, m), 1.02-1.40 (6H, m), 2.90-3.20 (3H,m), 3.32 (1H, d, J=8 Hz), 3.82-3.98 (1H, m), 4.12-4.22 (1H, m), 4.55(1H, s), 4.65 (1H, s), 5.95 (1H, s), 5.96 (1H, s), 6.70-7.18 (12H, m)

ESI-MS (m/z): 510 [M+H]

Example 35

[(2RS,3RS)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-Trp-NHSO₂CH₃(190 mg) was separated by using preparative TLC (benzene:ethylacetate:acetic acid=20:20:1) to give[(2R,3R)-2-(3,4-methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-Trp-NHSO₂CH₃(75 mg) as a less polar isomer, as an amorphous powder.

Rf: 0.57 (benzene:ethyl acetate:acetic acid=20:20:1)

NMR (CDCl₃, δ): 0.84 (3H, t, J=7 Hz), 1.11-1.42 (6H, m), 3.09 (3H, s),3.13-3.38 (3H, m), 3.98-4.09 (1H, m), 4.63-4.72 (1H, m), 5.94 (2H, s),6.32 (1H, d, J=8 Hz), 6.52-6.68 (3H, m), 6.90 (1H, d, J=4 Hz), 7.09 (1H,t, J=7 Hz), 7.20 (1H, t, J=7 Hz), 7.35 (1H, d, J=8 Hz), 7.43 (1H, d, J=8Hz), 8.26 (1H, s)

ESI-MS: 530 [M+H]

Example 36

[(2R,3R)-2-(3,4-Methylenedioxyphenyl)-3-hydroxyoctanoyl]-L-Trp(CH₂COOH)-NHSO₂CH₃(118 mg) was obtained according to a similar manner to that of Example14-1) from[(2R,3R)-2-(3,4-methylenedioxyphenyl)-3-hydroxyoctanoyl]-L-Trp(CH₂COOEt)-NHSO₂CH₃

NMR (DMSO-d₆, δ): 0.80 (3H, t, J=7 Hz), 0.94-1.46 (8H, m), 3.00 (3H, s),3.02-3.18 (2H, m), 3.37-3.48 (1H, m), 3.86-3.98 (1H, m), 4.50-4.70 (1H,m), 4.75-5.00 (3H, m), 5.96 (1H, s), 6.74 (1H, d, J=7 Hz), 6.80 (1H, d,J=7 Hz), 6.86 (1H, s), 6.96-7.40 (5H, m), 7.56-7.72 (1H, m), 8.27 (1H,d, J=7 Hz)

ESI-MS (m/z) 602 [M+H]

What is claimed is:
 1. A compound represented by the formula:

or a pharmaceutically acceptable salt thereof, wherein R¹ is loweralkyl, cyclo(lower)alkyl, optionallyy substituted aryl,cyclo(lower)alky(lower)alkyl, or ar(lower)alkyl, R² is hydroxy orprotected hydroxy, R³ is lower alkyl, aryl, ar(lower)alkyl, oroptionally substituted heterocyclic-(lower)alkyl, R⁴ is carboxy,protected carboxy or lower alkylsulfonylcarbamoyl, R⁵ is hydrogen orlower alkyl, A is a single bond or lower alkylene, and Ar is optionallysubstituted aryl.
 2. The compound of claim 1, wherein R¹ is lower alkyl,cyclo(lower)alkyl, or C₆-C₁₀ aryl optionally substituted by a groupselected from the group consisting of hydroxy, protected hydroxy,halogen, lower alkoxy, carboxy, protected carboxy, lower alkylenedioxy,carbamoyl(lower)alkyl, N- or N,N-di(lower)alkylcarbaamoyl(lower)alkyl,carboxy(lower)alkyl, protected carboxy(lower)alkyl, C₆-C₁₀ar(lower)alkyl, halo (lower) alkyl, halo (lower) alkoxy, lower alkanoyl,lower alkyl and C₆-C₁₀ aryl, R³ is lower alkyl, C₆-C₁₀ aryl, C₆-C₁₀ar(lower)alkyl or heterocyclic(lower)alkyl optionally substituted by agroup selected from the group consisting of hydroxy, protected hydroxy,halogen, lower alkoxy, carboxy, protected carboxy, lower alkylenedioxy,carbamoyl(lower)alkyl, N- or N,N- di(lower)alkylcarbamoyl(lower)alkyl,carboxy(lower)alkyl, protected carboxy(lower)alkyl, C₆₋C₁₀ar(lower)alkyl, halo(lower)alkyl, halo (lower)alkoxy, lower alkanoyl andlower alkyl, said heterocyclic group being unsaturated condensed 7- to12-membered heterocyclic group containing 1 to 5 nitrogen atom(s),unsaturated condensed 7- to 12-membered heterocyclic group containing 1to 3 sulfur atom(s) or its S,S-dioxide, unsaturated 3- to 8-memberedheteromonocyclic group containing 1 to 4 nitrogen atom(s), saturated 3-to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s),unsaturated condensed 7- to 12-membered heterocyclic group containing 1to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), unsaturated 3- to8-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1to 3 nitrogen atom(s), saturated 3- to 8-membered heteromonocyclic groupcontaining 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s),unsaturated condensed 7- to 1 2-membered heterocyclic group containing 1to 2 sulfur atom(s)and 1 to 3 nitrogen atom(s), unsaturated 3- to8-membered heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1to 3 nitrogen atom(s), saturated 3 to 8-membered heteromonocyclic groupcontaining 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), orunsaturated 3- to 8-membered heteromonocyclic group containing a sulfuratom, R² is hydroxy or lower alkanoyloxy, R⁴ is carboxy, loweralkoxycarbonyl, phenyl(lower)alkoxycarbonyl or alkyl sulfonylcarbamoyl,R⁵ is hydrogen, and Ar is C₆-C₁₀ aryl optionally substituted by a groupselected from the group consisting of hydroxy, protected hydroxy,halogen, lower alkoxy, carboxy, protected carboxy, lower alkylenedioxy,carbamoyl(lower)alkyl, N- or N,N-di(lower)alkylcarbamoyl(lower)alkyl,carboxy(lower)alkyl, protected carboxy(lower)alkyl, C₆-C₁₀ar(lower)alkyl, halo (lower) alkyl, halo (lower) alkoxy, lower alkanoyl,lower alkyl and C₆-C₁₀ aryl.
 3. The compound of claim 2, wherein R¹ islower alkyl, cyclo(lower)alkyl, or C₆-C₁₀ aryl optionally substituted bya group selected from the group consisting of lower alkoxy, carboxy,protected carboxy, lower alkylenedioxy and C₆-C₁₀ aryl, R³ is loweralkyl, C₆-C₁₀ aryl, C₆-C₁₀ ar(lower)alkyl or heterocyclic(lower)alkyloptionally substituted by a group selected from the group consisting ofprotected carboxy, carbamoyl(lower)alkyl, N- or N,N-di(lower)alkylcarbamoyl(lower)alkyl, carboxy(lower)alkyl, protectedcarboxy(lower)alkyl, lower alkanoyl and lower alkyl, said heterocyclicgroup being unsaturated bicyclic 9- or 10-membered heterocyclic groupcontaining 1 to 5 nitrogen atom(s), or unsaturated bicyclic 9- or10-membered heterocyclic group containing 1 to 3 sulfur atom(s) or itsS,S- dioxide, and Ar is C₆-C₁₀ aryl optionally substituted by a groupselected from the group consisting of hydroxy, protected hydroxy, loweralkoxy, carboxy, protected carboxy and lower alkylenedioxy.
 4. Thecompound of claim 3, wherein R¹ is lower alkyl, cyclo(lower)alkyl, orphenyl optionally substituted by a group selected from the groupconsisting of lower alkoxy, carboxy, lower alkoxycarbonyl, loweralkylenedioxy and phenyl, R² is hydroxy or lower alkanoyloxy, R³ islower alkyl, phenyl, phenyl(lower)alkyl, naphthyl(lower)alkyl, orheterocyclic(lower)alkyl optionally substituted by a group selected fromthe group consisting of lower alkoxycarbonyl, carbamoyl(lower)alkyl,N,N-di(lower)alkylcarbamoyl(lower)alkyl, carboxy(lower)alkyl, loweralkoxycarbonyl(lower)alkyl, phenyl(lower)alkoxycarbonyl(lower)alkyl,lower alkanoyl and lower alkyl, said heterocyclic group being indolyl orbenzothienyl or its S,S-dioxide Ar is phenyl or naphthyl, each of whichis optionally substituted by a group selected from the group consistingof hydroxy, phenyl(lower)alkoxy, lower alkoxy, carboxy, loweralkoxycarbonyl, phenyl(lower)alkoxycarbonyl and lower alkylenedioxy. 5.The compound of claim 4, wherein R¹ is lower alkyl, cyclo(lower)alkyl,or phenyl optionally substituted by a group selected from the groupconsisting of lower alkoxy, carboxy, lower alkoxycarbonyl, loweralkylenedioxy and phenyl, R³ is lower alkyl, phenyl, phenyl(lower)alkyl,naphthyl(lower)alkyl, indolyl(lower)alkyl, optionally substituted by agroup selected from the group consisting of lower alkoxycarbonyl,carbamoyl(lower)alkyl, N,N-di(lower)alkylcarbamoyl(lower)alkyl,carboxy(lower)alkyl, lower alkoxycarbonyl(lower)alkyl,phenyl(lower)alkoxycarbonyl(lower)alkyl, lower alkanoyl and lower alkyl,or benzothienyl(lower)alkyl or its S,S-dioxide, and Ar is phenyloptionally substituted by a group selected from the group consisting ofhydroxy, phenyl(lower)alkoxy, lower alkoxy, carboxy,phenyl(lower)alkoxycarbonyl and lower alkylenedioxy, or naphthyl.
 6. Thecompound of claim 5, wherein R³ is optionally substituted indolyl-loweralkyl.
 7. The compound of claim 6, wherein R³ is indolyl-lower alkylsubstituted with a lower alkyl group.
 8. The compound of claim 7, whichisN-[(2R,3R)-2-(3,4-methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-Trp(Me)-OH.9. The compound of claim 1, which is represented by the formula:

wherein Ar, A, R¹, R², R³, R⁴ and R⁵ are as defined in claim
 1. 10. Apharmaceutical composition which comprises a compound of claim 1, or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier or excipient.
 11. A method of treating an endothelinmediated disease, comprising administering an effective amount of thecompound of claim 1 or a pharmaceutically acceptable salt thereof to ahuman being or an animal in need thereof.